Topiramate oral liquid suspension and use thereof

ABSTRACT

Provided herein is an oral liquid suspension that includes topiramate, as well as methods of medical treatment that include orally administering the oral liquid suspension.

RELATED U.S. APPLICATION DATA

This application is a continuation-in-part (CIP) of patent applicationSer. No. 16/946,132 filed Jun. 8, 2020 which application claims priorityto provisional patent application No. 62/858,415 filed on Jun. 7, 2019;the contents of which are incorporated by reference herein in itsentirety.

BACKGROUND OF THE INVENTION

Epilepsy is a disease of the nervous system which is caused by braindysfunction due to excessive discharge of the nerve cells in the brain.It is estimated that the incidence rate of epilepsy is from about 0.3%to 0.5% globally. The morbidity rate is from about 5 to 10 people per1000 people. Epilepsy is a serious threat to people's health and affectstheir daily lives.

Topiramate is an antiepileptic drug and its chemical structure relatesto amino-sulfamate monosaccharide. Topiramate was first developed byJohnson & Johnson Company, Inc. USA. It was marketed under the brandname of Topamax in the UK in 1995. Based on in-vitro studies of neuronsin electrophysiological and biochemical experiments, it was found thatthere were three mechanisms of antiepileptic action. Firstly, topiramateblocks the neuron's depolarization, which indicates that it can blocksodium channels. Secondly, topiramate can increase the frequency ofactivation of γ-aminobutyrate (GABA) receptors by GABA and enhance theability of influx of chloride ions which indicates that topiramate canenhance the role of inhibitory central neurotransmitters. Thirdly,topiramate can reduce the activity of glutamate AMPA receptors whichindicates that topiramate can reduce the effect of excitatory centralneurotransmitters.

Topiramate is a white crystalline powder with a bitter taste. It isfreely soluble in acetone, dimethyl sulfoxide, ethanol, and alkalinesolutions containing sodium hydroxide or sodium phosphate. Itssolubility in water is approximately 9.8 mg/mL at room temperature.

Thus, to obtain a topiramate formulation with stable chemical propertiesand/or desired sustained release effect is highly desirable.

SUMMARY OF THE INVENTION

The present invention provides for an oral liquid suspension thatincludes: topiramate, preservative, sweetener, solvent, anticakingagent, viscosifying agent, suspending agent, pH adjuster, andtaste-masking agent.

The present invention also provides for an oral liquid suspension thatincludes: topiramate, preservative, sweetener, solvent, anticakingagent, viscosifying agent, suspending agent, flavoring agent, colorant,pH adjuster, and taste-masking agent.

The present invention also provides for an oral liquid suspension thatincludes: 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate(topiramate); water; glycerin; propylene glycol; polyethylene glycol;methylparaben; sodium benzoate; sorbitol; saccharin; sucralose; xanthangum; carboxymethyl cellulose (CMC); sodium phosphate; and PROSOLV® SMCC50M (microcrystalline cellulose and colloidal silicon dioxide).

The present invention also provides for an oral liquid suspension thatincludes:

Amount (% w/v) Component  2.5 ± 0.25 topiramate 0.10 ± 0.01methylparaben  0.03 ± 0.003 sodium benzoate powder  0.08 ± 0.008saccharin sodium dihydrate 3.00 ± 0.3  70% solution of sorbitol 2.25 ±0.3  propylene glycol  5 ± 0.5 glycerin (99% natural) 1.26 ± 0.15PROSOLV ® SMCC 50M (microcrystalline cellulose and colloidal silicondioxide) 0.18 ± 0.02 sodium carboxymethyl cellulose (medium viscosity,2% aqueous solution at 25° C. 400-800 cPs) 0.18 ± 0.02 xanthan gum NF0.20 ± 0.02 cherry flavor, natural & artificial  0.002 ± 0.0002 FD&C Red#40  0.0002 ± 0.00002 FD&C Yellow #6 79.67 ± 8.0  purified water  5 ±0.5 polyethylene glycol 400 0.25 ± 0.03 sodium phosphate dibasic (dried) 0.5 ± 0.05 sucralose

The composition described herein is an oral liquid suspension and not,e.g., an oral solution. As such, the active ingredient, topiramate, isnot fully dissolved but is essentially suspended therein. While theactive ingredient may be only slightly dissolved therein, the lack of itbeing fully dissolved could otherwise pose stability issues. As an oralliquid suspension, the active ingredient will typically settle to thebottom of the container during extended periods of time during theshipmen and storage. Effectively resuspending the active ingredient willneed to be carried out prior to use. Additionally, the active ingredient(topiramate) is unpleasant tasting.

The composition described herein is an oral liquid suspension thatincludes a suspending agent, viscosifying agent, anticaking agent, andredispersing agent. Achieving a suitable stability of the suspendedactive ingredient is achieved in part by modifying the pH of thecomposition. Achieving a suitable stability of the suspended activeingredient is also achieved in part by controlling the particle siredistribution as well as the water content of the active ingredient.Including a suitable flavoring agent provides a composition that isrelatively pleasant tasting. The oral liquid suspension, compared to thesolid oral dosage form (e.g., tablets) containing topiramate, istherefore (i) convenient to use, (ii) has a relatively quick onset ofaction, (iii) can be used with children and the elderly who often havedifficulties swallowing, and (iv) the dose can readily be titrated.Additionally, the above is achieved while providing for an oral liquidsuspension (v) having a suitable redispersibility, (vi) is relativelystable, (vii) is relatively pleasant tasting, (viii) upon shaking willbe substantially devoid of lumps or clumps, even after long storage,(ix) possesses good pourability, (x) has good physical stabilityproperties such as low level of sedimentation (reduced or no caking),(xi) has easy redispersion on agitation, and (xii) provides for doseuniformity during each administration.

The present invention also provides for a method for deliveringtopiramate to a subject in need thereof. The method includesadministering to the subject an oral liquid suspension described herein.

The present invention also provides for a method for treating at leastone of a neurological disorder and a mental disorder in a subject. Themethod includes administering to a subject suffering from the disorderan oral liquid suspension described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be more readily understood by reading thefollowing detailed description of the invention and study of theincluded examples.

The present invention is based, in part, upon the discovery of noveloral liquid suspensions that provide advantages when used for the invivo delivery to a mammal of the active pharmaceutical ingredient (API)topiramate. In doing so, the present invention provides for oral liquidsuspensions that provide for a suitable therapeutic index and/or lowerincidence, severity, or duration of adverse reaction(s) compared topreviously described dosage forms containing the active ingredient inthe same amount.

The oral liquid suspensions may be used for a variety of purposes,including for the in vivo delivery of the active pharmaceuticalingredient (API) topiramate. Accordingly, the present invention furtherprovides methods of treating diseases or disorders (e.g., neurologicaldisorder and/or a mental disorder), such as epilepsy and/or bipolardisorder.

Relative to oral tablets or chewable dispersible tablets containing anequivalent amount of topiramate, administration of the oral liquidsuspension may result in a lower incidence, severity, and/or duration ofadverse reactions including at least one of dizziness, headache,diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis,pharyngitis, rash, vomiting, infection, fever, accidental injury,diarrhea, abdominal pain, tremor, insomnia, somnolence, backpain,fatigue, abdominal pain, and xerostomia.

In forming an oral liquid suspension, any one or more of the excipientsemployed can effectively be dissolved or dispersed therein (e.g., in thesolvent). This includes, e.g., salts, such as sodium benzoate, saccharinsodium, and sodium carboxymethyl cellulose. In doing so, the salt candissociate into the respective anion and cation, and would therefore nolonger necessarily exist in the salt form—benzoic acid, saccharin, andcarboxymethyl cellulose. However, within the context of the invention,it is appreciated that those of skill in the art understand and agreethat reference to the oral liquid suspension as containing the salt formis otherwise acceptable and appropriate.

Likewise, in specific embodiments, topiramate: (having a specifiedparticle size distribution (PSD)) can be employed in the manufacture ofthe oral liquid suspension. In forming the oral liquid suspension, thetopiramate present therein can effectively be suspended and/or dissolvedtherein (e.g., in the solvent). In doing so, the topiramate wouldtherefore no longer necessarily retain the PSD. However, within thecontext of the invention, it is appreciated that those of skill in theart understand and agree that reference to the oral liquid suspension ascontaining the topiramate as having a specified PSD (based on thetopiramate employed) is otherwise acceptable and appropriate.Alternatively, reference to the oral liquid suspension as containing thetopiramate as having a specified PSD (based on the topiramate present inthe oral liquid suspension) is also acceptable and appropriate. As such,the PSD of the topiramate employed is often a parameter for the PSD oftopiramate present in the oral liquid suspension.

As used herein, “oral liquid suspension comprising” or “oral liquidsuspension that includes” refers to an oral liquid suspensionmanufactured from the specified ingredients. While the oral liquidsuspension may include such ingredients, it is appreciated that those ofskill in the art understand that one or more of the specified substancesmay not exist in that form, within the oral liquid suspension. However,reference to the oral liquid suspension as containing that substance isotherwise acceptable. By way of illustration, a powder may fullydissolve in the oral liquid suspension. As such, the powder form may nolonger exist in the oral liquid suspension. However, reference to theoral liquid suspension as containing a powder is readily understood bythe skilled artisan.

The articles “a” and “an” as used herein refers to “one or more” or “atleast one,” unless otherwise indicated. That is, reference to anyelement or component of an embodiment by the indefinite article “a” or“an” does not exclude the possibility that more than one element orcomponent is present.

The term “excipient” refers to a pharmacologically inactive componentpresent in the oral liquid suspension. Excipients include, e.g.,preservatives, sweetening agents, solvents, anticaking agents,viscosity-increasing agents, suspending agents, acidifying agents,taste-masking agents, flavoring agents, and colorants. The excipientsused in preparing the oral liquid suspension described herein are safeand non-toxic. Suitable excipients are disclosed in Handbook ofPharmaceutical Excipients, Rowe et al., Eds., 8th Edition,Pharmaceutical Press (2017).

One or more excipients employed in the oral liquid suspensions describedherein can have a single use. For example, when present in the oralliquid suspension described herein, methylparaben can function as apreservative; saccharin sodium dihydrate powder, sucralose, and sorbitolcan each function as a sweetening agent; topirimate can function as anactive pharmaceutical ingredient (API); sodium benzoate can function asa preservative; disodium phosphate can function as a pH modifying agent;cherry flavor (natural and artificial) can function as a flavoringagent; and/or FD&C red #410 and FD&C yellow #6 can function as acolorant.

Additionally, one or more excipients employed in the oral liquidsuspensions described herein can have a single, or multiple uses. Forexample, microcrystalline cellulose can function as a suspending agent,texturizer, anti-caking agent, or any combination thereof; propyleneglycol can function as a preservative, solvent, viscosity-increasingagent, or any combination thereof; polyethylene glycol can function as asolvent, viscosity-increasing agent, suspending agent, or anycombination thereof; glycerin can function as a preservative, sweeteningagent, solvent, viscosity-increasing agent, or any combination thereof;and/or xanthan gum can function as a viscosity-increasing agent,suspending agent, or a combination thereof.

In specific embodiments, the present invention provides for an oralliquid suspension that includes topirimate, preservative, sweetener,solvent, anticaking agent, viscosifying agent, suspending agent, pHadjuster, and taste-masking agent. It is contemplated that one or moreexcipients can be employed in the oral liquid suspension to effectivelyserve multiple functions. Specifically, a single excipient can functionas a preservative, solvent, and viscosity-increasing agent. Further, asingle excipient can function as a preservative, sweetening agent,solvent, and viscosity-increasing agent. Excipients useful in the oralliquid suspensions described herein, having multiple functions, aredescribed in Handbook of Pharmaceutical Excipients, Rowe et al., Eds.,8th Edition, Pharmaceutical Press (2017).

The term “preservative” refers to a substance that is added to products,such as oral liquid suspensions, to prevent decomposition by microbialgrowth or by undesirable chemical changes. In general, preservation isimplemented in two modes, chemical and physical. Suitable preservativesinclude, e.g., one or more of ethanol, benzoic acid, benzyl alcohol,bronopol, butylated hydroxyanisole (BHA), butylparaben, calcium acetate,calcium chloride, calcium lactate, cetrimide, cetylpyridinium chloride,chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acidmonohydrate, ethylparaben, glycerin, hexetidine, imidurea, isopropylalcohol, lactic acid, methylparaben, monothioglycerol, parabens,pentetic acid, phenoxyethanol, phenylethyl alcohol, potassium benzoate,potassium metabisulfite, potassium sorbate, propionic acid, propylgallate, propylene glycol, propylparaben, propylparaben sodium, sodiumacetate, sodium benzoate, sodium borate, sodium lactate, sodiummetabisulfite, sodium propionate, sodium sulfite, sorbic acid,sulfobutyl ether ß-cyclodextrin, edetic acid, thimerosal, and xanthan.

The term “sweetening agent” or “sweetener” refers to a substance that isadded to products, such as oral liquid suspensions, to provide a sweettaste like that of sugar. The sweetener can include, e,g., one or moreof acesulfame potassium, alitame, aspartame, dextrose, erythritol,fructose, glycerin, isomalt, lactitol, glucose, maltitol, maltose,mannitol, monk fruit extract, neohesperidin dihydrochalcone, neotame,saccharin, saccharin sodium, sodium cyclamate, sorbitol, stevia,sucralose, sucrose, tagatose, thaumatin, trehalose, and xylitol.

The term “solvent” refers to a substance that is added to products, suchas oral liquid suspensions, to dissolve the active pharmaceuticalingredient (API) and/or excipients. The solvent can include, e.g., oneor more of albumin, ethanol, almond oil, benzyl alcohol, benzylbenzoate, butylene glycol, castor oil, corn oil (maize), cottonseed oil,dimethyl ether, dimethylacetamide, ethyl lactate, ethyl oleate,glycerin, isopropyl alcohol, isopropyl myristate, isopropyl palmitate,light mineral oil, medium-chain triglycerides, methyl lactate, mineraloil, monoethanolamine, octyldodecanol, olive oil, peanut oil,polyethylene glycol, polyoxyl castor oil, propylene carbonate, propyleneglycol, pyrrolidone, safflower oil, sesame oil, soybean oil, sunfloweroil, triacetin, tricaprylin, triethanolamine, triethyl citrate,triolein, and water.

The term “anticaking agent” refers to a substance that is added toproducts, such as oral liquid suspensions, to prevent or decrease theoccurrence of agglomeration of particles, such as the activepharmaceutical ingredient (API) and/or excipients. The anticaking agentis added to prevent or decrease the formation of lumps (caking), whichprovides for ease in packaging, transport, flowability, and consumption.The anticaking, agent can include, e.g., one or more of tribasic calciumphosphate, calcium silicate, colloidal silicon dioxide, hydrophobiccolloidal silica, magnesium oxide, magnesium silicate, magnesiumtrisilicate, and talc.

The term “viscosity-increasing agent” refers to a substance that isadded to products, such as oral liquid suspensions, to increase theviscosity. The viscosity increasing agent is used in order to impart anappropriate viscosity to the oral liquid suspension. The viscosityincreasing agent increases the viscosity of the oral liquid suspensionwithout substantially changing its other properties. Theviscosity-increasing agent can include, e.g, one or more of acacia,agar, alginic acid, bentonite, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carrageenan, ceratonia, cetostearylalcohol, chitosan, colloidal silicon dioxide, cyclomethicone,ethylcellulose, gelatin, glycerin, guar gum, hectorite, hydrogenatedvegetable oil type I, hydrophobic colloidal silica, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose,hydroxypropyl starch, hypromellose, magnesium aluminum silicate,maltodextrin, methylcellulose, myristyl alcohol, polydextrose,polyethylene glycol, polyvinyl alcohol, potassium chloride, povidone,propylene glycol alginate, saponite, sodium alginate, sodium chloride,starch, stearyl alcohol, sucrose, sulfobutyl ether ß-cyclodextrin,tragacanth, and xanthan gum.

The term “suspending agent” refers to a substance that helps the activepharmaceutical ingredient (API) stay suspended in the oral liquidsuspension and prevents caking at the bottom of the container. One ofthe properties of a well-formulated oral liquid suspension is that itcan be easily re-suspended by the use of moderate agitation or shaking.The suspending agent can include, e.g., one or more of acacia, agar,alginic acid, bentonite, calcium stearate, carbomers,carboxymethylcellulose calcium, carboxymethylcellulose sodium,carrageenan, powdered cellulose, cellulose, microcrystalline cellulose,carboxymethylcellulose sodium, ceratonia, colloidal silicon dioxide,dextrin, gelatin, guar gum, hectorite, hydrophobic colloidal silica,hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose, hypromellose, kaolin, magnesium aluminum silicate, maltitolsolution, medium-chain triglycerides, methylcellulose, silicifiedmicrocrystalline cellulose, phospholipids, polycarbophil, polyethyleneglycol, polyoxyethylene sorbitan fatty acid esters, potassium alginate,povidone, propylene glycol alginate, saponite, sesame oil, sodiumalginate, sodium starch glycolate, sorbitan esters, sucrose, tragacanth,vitamin E polyethylene glycol succinate, and xanthan gum. Additionally,the suspending agent can include, e.g., PROSOLV® SMCC 50M(microcrystalline cellulose and colloidal silicon dioxide).

The suspending agent is able to reduce the formation of topiramatehydrate. In some embodiments, less than about 8 wt. %, less than about 5wt. %, less than about 3 wt. %, less than about 1 wt. %, or less thanabout 0.5 wt. % of the topiramate thereof is converted into its hydrateform over the period of time of manufacturing, shipping, and storage ofthe oral liquid suspension described herein (e.g., up to 6-9 months)under ambient conditions.

The suspending agent also contributes to the stability of the suspensionafter reconstitution. In some embodiments, less than about 5 wt. %, lessthan about 3 wt. %, less than about 1 wt. %, less than about 0.5 wt. %,less than about 0.2 wt. %, or less than about 0.1 wt. % of thetopiramate is decomposed over the period of time of manufacturing,shipping, and storage of the oral liquid suspension described herein(e.g., up to 6-9 months) under ambient conditions.

The term “acidifying agent” refers to a substance that is added toproducts, such as oral liquid suspensions, to lower the pH, or is addedto achieve a desired pH that is lower than it would otherwise be in theabsence of the acidifying agent. The acidifying agent can include, e.g.,one or more of sodium phosphate dibasic, adipic acid, ammonium chloride,citric acid monohydrate, diluted hydrochloric acid, lactic acid,propionic acid, and tartaric acid.

The term “flavoring agent” refers to a substance that gives anothersubstance flavor, altering the characteristics of the solute, causing itto become sweet, sour, tangy, etc. A flavor is a quality of somethingthat affects the sense of taste. The flavoring agent can include, e.g.,cherry flavor, grape, or peppermint.

The term “colorant” or “coloring agent” refers to substance that isadded or applied in order to change the color of a material or surface.Colorants work by absorbing varying amounts of light at differentwavelengths (or frequencies) of its spectrum, transmitting (iftranslucent) or reflecting the remaining light in straight lines orscattered. The colorant can include, e.g., FD&C red #40, FD&C yellow #6,or a combination thereof.

The term “oral liquid suspension” refers to a pharmaceutical dosage formthat is a liquid and is orally administered. It includes topiramatemixed with a liquid vehicle for oral administration. Being a suspension,the dosage form consists of undissolved particles (e.g., topiramateand/or excipients). The undissolved particles can be suspended in theoral liquid suspension. Alternatively, the undissolved particles cansettle to the bottom of the container where it can be shaken and/oragitated to resuspend in the solution.

The term “topiramate” refers to the compound chemically designated as2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate. Topiramate hasthe molecular formula C₁₂H₂₁NO₈S and a molecular weight of 339.36. Inspecific embodiments, the topiramate functions as the sole activeingredient. The topiramate used herein will also have a suitableparticle size distribution (PSD). Topiramate, unless otherwisespecified, includes the free base, pharmaceutically acceptable saltsthereof, isomers, and polymorphs thereof. Topiramate is commerciallyavailable in multiple physical forms (e.g., amorphous or crystallineforms). A micronized amorphous form is commercially available fromPolpharma (Poland).

The term “glycerin” or “glycerol” refers to the compound chemicallydesignated as propane-1,2,3-triol, having the chemical formula C₃H₈O₃and molar mass 92.094 g/mol. The glycerin can be glycerin, 99% natural.When present in the oral liquid suspension described herein, theglycerin can function as a preservative, sweetening agent, solvent,viscosity-increasing agent, or any combination thereof.

The term “propylene glycol” refers to the compound chemically designatedas propane-1,2-diol, having the chemical formula C₃H₈O₂, and molar mass76.095 g/mol. When present in the oral liquid suspension describedherein, the propylene glycol can function as a preservative, solvent,viscosity-increasing agent, or any combination thereof.

The term “polyethylene glycol” or “PEG” refers to the compoundchemically designated as polyoxyethylene) or PEO (also referred to aspolyethylene oxide) or PEO), having the chemical formulaC_(2n)H_(4n+2)O_(n+1), and molar mass 18.02+44.05n g/mol. PEG, PEO, andPOE refer to an oligomer or polymer of ethylene oxide. The three namesare chemically synonymous, but historically PEG is preferred in thebiomedical field, whereas PEO is more prevalent in the field of polymerchemistry. Because different applications require different polymerchain lengths, PEG has tended to refer to oligomers and polymers with amolecular mass below 20,000 g/mol, PEO to polymers with a molecular massabove 20,000 g/mol, and POE to a polymer of any molecular mass. PEGs aretypically prepared by polymerization of ethylene oxide and arecommercially available over a wide range of molecular weights from 300g/mol to 10,000,000 g/mol. When present in the oral liquid suspensiondescribed herein, the polyethylene glycol can function as a solvent,viscosity-increasing agent, suspending agent, or any combinationthereof.

The polyethylene glycol can be polyethylene glycol 400. The term“polyethylene glycol 400” refers to a low-molecular-weight grade ofpolyethylene glycol, having the chemical formula C_(2n)H_(4n+2)O_(n+1),wherein n=8.2 to 9.1, and molar mass 380-420 g/mol. When present in theoral liquid suspension described herein, the polyethylene glycol 400 canfunction as a solvent, viscosity-increasing agent, suspending agent, orany combination thereof.

The term “methylparaben” refers to the compound chemically designated asmethyl 4-hydroxybenzoate, having the chemical formula C₈H₈O₃, and molarmas 152.149 g/mol. When present in the oral liquid suspension describedherein, the methylparaben can function as a preservative.

The term “sodium benzoate” refers to the compound benzoate of soda,having the chemical formula C₇H₅NaO₂, and molar mass 144.105 g/mol. Whenpresent in the oral liquid suspension described herein, the sodiumbenzoate can function as a preservative.

The term “sorbitol” refers to the compound chemically designated as(2S,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol, having the chemical formulaC₆H₁₄O₆, and molar mass 182.17 g/mol. The sorbitol can be solidsorbitol. Alternatively, the sorbitol can be in solution (e.h., 70%solution of sorbitol). When present in the oral liquid suspensiondescribed herein, the sorbitol can function as a sweetening agent.

The term “saccharin” refers to the compound chemically designated as1,1-dioxo-1,2-benzothiazol-3-one, having the chemical formula C₇H₅NO₃S,and molar mass 183.18 g/mol. When present in the oral liquid suspensiondescribed herein, the saccharin can function as a sweetening agent.

The saccharin can be saccharin sodium dihydrate powder. The term“saccharin sodium” refers to the sodium salt of saccharin. When presentin the oral liquid suspension described. herein, the saccharin sodiumdihydrate powder can function as a sweetening agent.

The term “sucralose” refers to the compound chemically designated as1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranoside,having the chemical formula C₁₂H₁₉Cl₃O₈, and molar mass 397.64 g/mol.When present in the oral liquid suspension described herein, thesucralose can function as a sweetening agent.

The term “citric acid” refers to the compound chemically designated as2-hydroxypropane-1,2,3-tri carboxylic acid, having the chemical formulaC₆H₈O₇, and molar mass 192.123 g/mol (anhydrous) or 210.038 g/mol(monohydrate). When present in the oral liquid suspension describedherein, the citric acid can function as an acidifying agent,preservative, or combination thereof.

The term “xanthan gum” refers to a polysaccharide having the CAS Number11138-66-2, and chemical formula C₃₅H₄₉O₂₉ (monomer). When present inthe oral liquid suspension described herein, the xanthan gum canfunction as a viscosity-increasing agent, suspending agent, or acombination thereof.

The term “carboxymethyl cellulose,” “carmellose,” or “CMC” refers to acellulose derivative with carboxymethyl groups (—CH₂—COOH) bound to someof the hydroxyl groups of the glucopyranose monomers that make up thecellulose backbone. It is often used as its sodium salt, sodiumcarboxymethyl cellulose. CMC has the CAS Number 9000-11-7. Thecarboxymethyl cellulose can be sodium carboxymethyl cellulose (mediumviscosity, 2% aqueous solution at 25° C. 400-800 cPs). When present inthe oral liquid suspension described herein, the carboxymethyl cellulosecan function as a viscosity-increasing agent, suspending agent, orcombination thereof.

The term “microcrystalline cellulose” or “MCC” is a term for refinedwood pulp. A naturally occurring polymer, it is composed of glucoseunits connected by a 1-4 beta glycosidic bond. These linear cellulosechains are bundled together as microfibril spiraled together in thewalls of plant cell. When present in the oral liquid suspensiondescribed herein, the microcrystalline cellulose can function as asuspending agent.

The term “silicified microcrystalline cellulose” refers to MCC which issilicified. Silicification is the process in which organic matterbecomes saturated with silica. When present in the oral liquidsuspension described herein, the silicified microcrystalline cellulosecan function as a suspending agent.

The term “disodium phosphate” or “DSP” or “sodium hydrogen phosphate” or“sodium phosphate dibasic” refers to the inorganic compound with theformula Na₂HPO₄. and CAS Number 7558-79-4. The disodium phosphate can besodium phosphate dibasic (dried). When present in the oral liquidsuspension described herein, the disodium phosphate can function as a pHmodifying agent.

The term “PROSOLV® SMCC” refers to silicified microcrystallinecellulose, which is a combination of microcrystalline cellulose (MCC)and colloidal silicon dioxide (CSD). The commercial product PROSOLV®SMCC 50M has an average particle size determined by laser diffraction(μm) of 65. The commercial product PROSOLV® SMCC 50M also has a bulkdensity (g/mL) of 0.25-0.37. PROSOLV® SMCC is commercially availablefrom JRS Pharma (Patterson, N.Y.), https://www.jrspharma.comlpharma_en/.

The term “neurological disorder” refers to any disorder of the nervoussystem. Structural, biochemical or electrical abnormalities in thebrain, spinal cord or other nerves can result in a range of symptoms.Such disorders may be diagnosed by a health care professional.

The term “mental disorder” or “psychiatric disorder” refers to abehavioral or mental pattern that causes significant distress orimpairment of personal functioning. Such features may be persistent,relapsing and remitting, or occur as a single episode. Many disordershave been described, with signs and symptoms that vary widely betweenspecific disorders. Such disorders may be diagnosed by a mental healthprofessional. The Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition (“DSM-5”) is the 2013 update to the Diagnostic andStatistical Manual of Mental Disorders, the taxonomic and diagnostictool published by the American Psychiatric Association (APA). In theUnited States, the DSM serves as the principal authority for psychiatricdiagnoses. Treatment recommendations are often determined by DSMclassifications.

The term “epilepsy” refers to a group of neurological disorderscharacterized by epileptic seizures. Epileptic seizures are episodesthat can vary from brief and nearly undetectable periods to long periodsof vigorous shaking. These episodes can result in physical injuries,including occasionally broken bones. In epilepsy, seizures tend to recurand, as a rule, have no immediate underlying cause. Isolated seizuresthat are provoked by a specific cause such as poisoning are not deemedto represent epilepsy. People with epilepsy may be treated differentlyin various areas of the world and experience varying degrees of socialstigma due to their condition.

The term “focal seizures” or “partial seizures” or “partial onsetseizures” refer to localized seizures and are seizures which affectinitially only one hemisphere of the brain. The brain is divided intotwo hemispheres, each consisting of four lobes—the frontal, temporal,parietal and occipital lobes. A focal seizure is generated in andaffects just one part of the brain—a whole hemisphere or part of a lobe.Symptoms will vary according to where the seizure occurs. In the frontallobe symptoms may include a wave-like sensation in the head; in thetemporal lobe, a feeling of déjà vu; in the parietal lobe, numbness ortingling; and in the occipital lobe, visual disturbance orhallucination.

The term “generalized seizures,” as opposed to focal seizures, refer toa type of seizure that impairs consciousness and distorts the electricalactivity of the whole or a larger portion of the brain (which can beseen, for example, on electroencephalography, EEG.

The term “generalized tonic-clonic seizure” or “grand mal seizure”refers to a type of generalized seizure that produces bilateral,convulsive tonic and clonic muscle contractions. Tonic-clonic seizuresare the seizure type most commonly associated with epilepsy and seizuresin general and the most common seizure associated with metabolicimbalances. A tonic-clonic seizure is a convulsion that combines thecharacteristics of tonic (meaning stiffening) and clonic (meaningrhythmical jerking) seizures. The disturbance in functioning is presentin both sides of the brain. The tonic phase comes first (e.g., all themuscles stiffen, air being forced past the vocal cords causes a cry orgroan, and the person loses consciousness and falls to the floor). Afterthe tonic phase comes the clonic phase (e.g., the arms and usually thelegs begin to jerk rapidly and rhythmically, bending and relaxing at theelbows, hips, and knees, and after a few minutes, the jerking slows andstops.).

The term “Lennox-Gastaut syndrome” refers to a complex, rare, and severechildhood-onset epilepsy. It is characterized by multiple and concurrentseizure types, cognitive dysfunction, and slow spike waves onelectroencephalogram (EEG). Typically, it presents in children aged 3-5years and can persist into adulthood. It has been associated withseveral gene mutations, perinatal insults, congenital infections, brainhumors/malformations, and genetic disorders such as tuberous sclerosisand West syndrome.

The term “generalized seizures of Lennox-Gastaut syndrome” refers togeneralized seizures associated with Lennox-Gastaut syndrome.

The term “antiepileptic drug,” “anticonvulsant,” or “AED” refers to adiverse group of pharmacological agents used in the treatment ofepileptic seizures. Anticonvulsants are also increasingly being used inthe treatment of bipolar disorder and borderline personality disorder,since many seem to act as mood stabilizers, and for the treatment ofneuropathic pain. Anticonvulsants suppress the excessive rapid firing ofneurons during seizures. Anticonvulsants also prevent the spread of theseizure within the brain.

The term “bipolar disorder,” previously known as manic depression,refers to a mental disorder that causes periods of depression andperiods of abnormally elevated mood. The elevated mood is significantand is known as mania or hypomania, depending on its severity, orwhether symptoms of psychosis are present. During mania, an individualbehaves or feels abnormally energetic, happy, or irritable. Individualsoften make poorly thought out decisions with little regard to theconsequences. The need for sleep is usually reduced during manic phases.During periods of depression, there may be crying, a negative outlook onlife, and poor eye contact with others.

The term “combination therapy,” “adjunctive therapy,” or “polytherapy”refers to therapy that uses more than one medication or modality (versus“monotherapy,” which is any therapy taken alone). Typically, these termsrefer to using multiple therapies to treat a single disease, and oftenall the therapies are pharmaceutical (although it can also involvenon-medical therapy, such as the combination of medications and talktherapy to treat depression). Monotherapy can be applied to anytherapeutic approach, but it is most commonly used to describe the useof a single medication. Typically, monotherapy is selected because asingle medication is adequate to treat the medical condition. However,monotherapies may also be used because of unwanted side effects ordangerous drug interactions.

The particle size of topiramate can be measured by suitable techniquessuch as laser light scattering (e.g. Malvern Light Scattering), Coultercounter, microscopy, Fraunhofer diffraction and any other techniqueknown in the art. This particle size can be obtained either by the finalstep during the manufacture of the topiramate or by the use ofconventional micronizing techniques after the crystallizationprocedure(s).

The term “T_(max)” refers to time of maximum plasma concentration and isthe time to reach maximum (peak) plasma concentration following drugadministration, It is measured in units of time (hours).

The term “t_(1/2)” refers to elimination half-life and is time to reachelimination half-life (to be used in one or non-compartmental model). Itis measured in units of time (hours).

The term “stable” refers to chemical stability, wherein not more than 5wt. % of total related substances are formed on storage at 40° C. and75% relative humidity (R.H.) for a period of 90 days.

The term “shaken” refers to shaken prior to use. For example, a medicalpractitioner or subject (e.g., patient) can shake the oral liquidsuspension prior to administration. The shaking can include vigorouslyshaking by hand, for example, for about 5 to 40 seconds.

The term “release,” “released,” “releasing,” and the like, when used inconnection with a pharmaceutical dosage form, refers to the process orthe portion of the active ingredient that leaves the dosage formfollowing contact with an aqueous environment. Unless otherwiseindicated, the quantity of an active ingredient released from a dosageform is measured by dissolution testing in water as described in thisinvention. The results of the dissolution testing are reported as apercentage (w/w) released as a function of time or as the release time,in some embodiments, complete release of an active ingredient occurswhen at least 90% of the active ingredient has been released from thedosage form.

The term “immediate-release” refers to those which disintegrate rapidlyand/or get dissolved to release the medicaments or active ingredient.

The term “sedimentation volume ratio” or “sedimentation ratio” refers toa ratio of the ultimate volume of sediment (Vu) to the original volumeof sediment (VO) before settling. The sedimentation volume ratio isgenerally achieved within about 5 minutes, 3 minutes, 2 minutes, 60seconds, 45 seconds, or 30 seconds after the powder formulation isreconstituted to the suspension. Various mechanical means, such asshaking, swirling, heating, or any combination thereof can be used topromote a uniform suspension.

The term “subject” refers to a mammal, such as an animal or a human.Hence, the methods disclosed herein can be useful in human therapy andveterinary applications. In one embodiment, the subject is an animal. Inanother embodiment, the subject is a human.

The term “treat” or “treating” refers to attain or attaining abeneficial or desired result, such as a clinical result. In someembodiments, the beneficial or desired result is any one or more of thefollowing: inhibiting or suppressing the onset or development of acondition, reducing the severity of the condition, reducing the numberor severity of symptoms associated with the condition, increasing thequality of life of a patient suffering from the condition, decreasingthe dose of another medication required to treat the condition,enhancing the effect of another medication a patient is taking for thecondition, and prolonging the survival of a patient having thecondition.

The term “D₉₀” refers to the particle size corresponding to 90% of thecumulative undersize distribution by volume.

The term “D₅₀” refers to the particle size corresponding to 50% of thecumulative undersize distribution by volume.

The term “D₁₀” refers to the particle size corresponding to 10% of thecumulative undersize distribution by volume.

It is appreciated that those of skill in the art understand that each ofthe excipients present in the oral liquid suspension provide for one ormore functions. For example, glycerin can function as a preservative,sweetening agent, solvent, viscosity-increasing agent, or anycombination thereof. Formulating an oral liquid suspension to containexcipients that provide multiple functions is beneficial andadvantageous, for example, as the oral liquid suspension can have apleasant taste and/or can have a higher drug load (thereby requiring alower volume to be administered), while achieving the desirablephysicochemical properties and technical attributes.

The viscosity can be measured by using as suitable instrument such asBrookfield viscometer, Haake VT 550 viscometer at room temperature (25°C.).

The oral liquid suspension described herein can be packaged in asuitable pack/container such as amber colored polyethylene terephthalate(PET) bottle, glass bottle, high density polyethylene (DPE) bottle, lowdensity polyethylene (LDPE) bottle, polypropylene (PP) bottle, the like.The glass or plastic bottle can be provided with a child proof closure.The package can include a syringe or cup (marked in mL, ounces, or both)for ease of dosing. The container such as bottle has a fill volume of,e.g., from about 50 mL to about 500 mL containing the topiramate oralliquid suspension. Containers for use in the storage of the oralsuspensions may be used to administer a multiple dose of topiramate.

Specific Ranges, Values, Features, and Embodiments

The specific embodiments provided below describing the ranges, values,and features are for illustration purposes only, and do not otherwiselimit the scope of the disclosed subject matter, as defined by theclaims.

In specific embodiments, the oral liquid suspension includes topiramate,present in 2.5±0.30% (w/v).

In specific embodiments, the oral liquid suspension includes topiramate,present in 2.5±0.25% (w/v).

In specific embodiments, the oral liquid suspension includes topiramate,present in 2.5±0.20% (w/v).

In specific embodiments, the oral liquid suspension includes topiramate,present in 2.5±0.15% (w/v).

In specific embodiments, the oral liquid suspension includes topiramate,present in 2.5±0.10% (w/v).

In specific embodiments, the oral liquid suspension includes topiramate,present in 2.5±0.05% (w/v).

In specific embodiments, the oral liquid suspension includes topiramate,present in 25 mg per milliliter.

In specific embodiments, the oral liquid suspension includes topiramate,present in 25±2.5 mg per milliliter.

In specific embodiments, the oral liquid suspension includes topiramate,present in 25±2.0 mg per milliliter.

In specific embodiments, the oral liquid suspension includes topiramate,present in 25±1.5 mg per milliliter.

In specific embodiments, the oral liquid suspension includes topiramate,present in 25±1.0 mg per milliliter.

In specific embodiments, the oral liquid suspension includes topiramate,present in 25±0.5 mg per milliliter.

In specific embodiments, the oral liquid suspension includes one or morepreservatives selected from ethanol, benzoic acid, benzyl alcohol,bronopol, butylated hydroxyanisole (BHA), butylparaben, calcium acetate,calcium chloride, calcium lactate, cetrimide, cetylpyridinium chloride,chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acidmonohydrate, ethylparaben, glycerin, hexetidine, imidurea, isopropylalcohol, lactic acid, methylparaben, monothioglycerol, parabens,pentetic acid, phenoxyethanol, phenylethyl alcohol, potassium benzoate,potassium metabisulfite, potassium sorbate, propionic acid, propylgallate, propylene glycol, propylparaben, propylparaben sodium, sodiumacetate, sodium benzoate, sodium borate, sodium lactate, sodiummetabisulfite, sodium propionate, sodium sulfite, sorbic acid,sulfobutyl ether ß-cyclodextrin, edetic acid, thimerosal, xanthan, andcombinations thereof.

In specific embodiments, the oral liquid suspension includes one or moresweeteners selected from acesulfame potassium, alitame, aspartame,dextrose, erythritol, fructose, glycerin, isomalt, lactitol, glucose,maltitol, maltose, mannitol, monk fruit extract, neohesperidindihydrochalcone, neotame, saccharin, saccharin sodium, sodium cyclamate,sorbitol, stevia, sucralose, sucrose, tagatose, thaumatin, trehalose,xylitol, and combinations thereof.

In specific embodiments, the oral liquid suspension includes one or moresolvents selected from albumin, ethanol, almond oil, benzyl alcohol,benzyl benzoate, butylene glycol, castor oil, corn oil (maize),cottonseed oil, dimethyl ether, dimethylacetamide, ethyl lactate, ethyloleate, glycerin, isopropyl alcohol, isopropyl myristate, isopropylpalmitate, light mineral oil, medium-chain triglycerides, methyllactate, mineral oil, monoethanolamine, octyldodecanol, olive oil,peanut oil, polyethylene glycol, polyoxyl castor oil, propylenecarbonate, propylene glycol, pyrrolidone, safflower oil, sesame oil,soybean oil, sunflower oil, triacetin, tricaprylin, triethanolamine,triethyl citrate, triolein, water, and combinations thereof.

In specific embodiments, the oral liquid suspension includes one or moreanticaking agents selected from tribasic calcium phosphate, calciumsilicate, colloidal silicon dioxide, hydrophobic colloidal silica,magnesium oxide, magnesium silicate, magnesium trisilicate, talc, andcombinations thereof.

In specific embodiments, the oral liquid suspension includes one or moreviscosity-increasing agents selected from acacia, agar, alginic acid,bentonite, carboxymethylcellulose calcium, carboxymethylcellulosesodium, carrageenan, ceratonia, cetostearyl alcohol, chitosan, colloidalsilicon dioxide, cyclomethicone, ethylcellulose, gelatin, glycerin, guargum, hectorite, hydrogenated vegetable oil type 1, hydrophobic colloidalsilica, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, magnesiumaluminum silicate, maltodextrin, methylcellulose, myristyl alcohol,polydextrose, polyethylene glycol, polyvinyl alcohol, potassiumchloride, povidone, propylene glycol alginate, saponite, sodiumalginate, sodium chloride, starch, stearyl alcohol, sucrose, sulfobutylether ß-cyclodextrin, tragacanth, xanthan gum, and combinations thereof.

In specific embodiments, the oral liquid suspension includes one or moresuspending agents selected from acacia, agar, alginic acid, bentonite,calcium stearate, carbomers, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carrageenan, powdered cellulose,cellulose, microcrystalline cellulose, carboxymethylcellulose sodium,ceratonia, colloidal silicon dioxide, dextrin, gelatin, guar gum,hectorite, hydrophobic colloidal silica, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose,kaolin, magnesium aluminum silicate, maltitol solution, medium-chaintriglycerides, methylcellulose, silicified microcrystalline cellulose,phospholipids, polycarbophil, polyethylene glycol, polyoxyethylenesorbitan fatty acid esters, potassium alginate, povidone, propyleneglycol alginate, saponite, sesame oil, sodium alginate, sodium starchglycolate, sorbitan esters, sucrose, tragacanth, vitamin E polyethyleneglycol succinate, and xanthan gum, PROSOLV® SMCC 50M (microcrystallinecellulose and colloidal silicon dioxide), and combinations thereof.

In specific embodiments, the oral liquid suspension includes one or moreacidifying agents selected from sodium phosphate dibasic, adipic acid,ammonium chloride, citric acid monohydrate, diluted hydrochloric acid,lactic acid, propionic acid, tartaric acid, and combinations thereof.

In specific embodiments, the oral liquid suspension includes one or moreflavoring agents selected from cherry flavor, grape, peppermint, andcombinations thereof.

In specific embodiments, the oral liquid suspension includes water,present in 79.67±10% (w/v).

In specific embodiments, the oral liquid suspension includes water,present in 79.67±8% (w/v).

In specific embodiments, the oral liquid suspension includes water,present in 79.67±7% (w/v).

In specific embodiments, the oral liquid suspension includes water,present in 79.67±5% (w/v).

In specific embodiments, the oral liquid suspension includes water,present in 79.67±3% (w/v).

In specific embodiments, the oral liquid suspension includes water,present in 79.67±1.5% (w/v).

In specific embodiments, the oral liquid suspension includes glycerin,present in 5±2.0% (w/v).

In specific embodiments, the oral liquid suspension includes glycerin,present in 5±1.0% (w/v).

In specific embodiments, the oral liquid suspension includes glycerin,present in 5±0.75% (w/v).

In specific embodiments, the oral liquid suspension includes glycerin,present in 5±0.50% (w/v).

In specific embodiments, the oral liquid suspension includes glycerin,present in 5±0.25% (w/v).

In specific embodiments, the oral liquid suspension includes propyleneglycol, present in 2.25±1.0% (w/v).

In specific embodiments, the oral liquid suspension includes propyleneglycol, present in 2.25±0.75% (w/v).

In specific embodiments, the oral liquid suspension includes propyleneglycol, present in 2.25±0.5% (w/v).

In specific embodiments, the oral liquid suspension includes propyleneglycol, present in 2.25±0.3% (w/v).

In specific embodiments, the oral liquid suspension includes propyleneglycol, present in 2.25±0.25% (w/v).

In specific embodiments, the oral liquid suspension includespolyethylene glycol 400, present in 5.00±2.0% (w/v).

In specific embodiments, the oral liquid suspension includespolyethylene glycol 400, present in 5.00±1.0% (w/v).

In specific embodiments, the oral liquid suspension includespolyethylene glycol 400, present in 5.00±0.75% (w/v).

In specific embodiments, the oral liquid suspension includespolyethylene glycol 400, present in 5.00±0.5% (w/v).

In specific embodiments, the oral liquid suspension includespolyethylene glycol 400, present in 5.00±0.25% (w/v).

In specific embodiments, the oral liquid suspension includesmethylparaben, present in 0.1±0.05% (w/v).

In specific embodiments, the oral liquid suspension includesmethylparaben, present in 0.1±0.04% (w/v).

In specific embodiments, the oral liquid suspension includesmethylparaben, present in 0.1±0.03% (w/v).

In specific embodiments, the oral liquid suspension includesmethylparaben, present in 0.1±0.02% (w/v).

In specific embodiments, the oral liquid suspension includesmethylparaben, present in 0.1±0.01% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumbenzoate powder, present in 0.03±0.006% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumbenzoate powder, present in 0.03±0.003% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumbenzoate powder, present in 0.03±0.002% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumbenzoate powder, present in 0.03±0.001% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.42% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.6% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.5% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.3% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.2% (w/v).

In specific embodiments, the oral liquid suspension includes sorbitol,present in 2.1±0.1% (w/v).

In specific embodiments, the oral liquid suspension includes a 70%solution of sorbitol, present in 3.0±0.6% (w/v).

In specific embodiments, the oral liquid suspension includes a 70%solution of sorbitol, present in 3.0±0.4% (w/v).

In specific embodiments, the oral liquid suspension includes a 70%solution of sorbitol, present in 3.0±0.2% (w/v).

In specific embodiments, the oral liquid suspension includes a 70%solution of sorbitol, present in 3.0±0.1% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.04% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.02% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.015% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.010% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.008% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.003% (w/v).

In specific embodiments, the oral liquid suspension includes saccharinsodium dihydrate powder, present in 0.08±0.012% (w/v).

In specific embodiments, the oral liquid suspension includes sucralose,present in 0.5±0.15% (w/v).

In specific embodiments, the oral liquid suspension includes sucralose,present in 0.5±0.10% (w/v).

-   In specific embodiments, the oral liquid suspension includes    sucralose, present in 0.5±0.05% (w/v).-   In specific embodiments, the oral liquid suspension includes    sucralose, present in 0.5±0.25% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumphosphate dibasic (dried), present in 0.25±0.08% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumphosphate dibasic (dried), present in 0.25±0.05% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumphosphate dibasic (dried), present in 0.25±0.03% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumphosphate dibasic (dried), present in 0.25±0.025% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumphosphate dibasic (dried), present in 0.2.5±0.02% (w/v).

In specific embodiments, the oral liquid suspension includes xanthangum, present in 0.18±0.10%.

In specific embodiments, the oral liquid suspension includes xanthangum, present in 0.18±0.08%.

In specific embodiments, the oral liquid suspension includes xanthangum, present in 0.18±0.05%.

In specific embodiments, the oral liquid suspension includes xanthangum, present in 0.18±0.03%.

In specific embodiments, the oral liquid suspension includes xanthangum, present in 0.18±0.02%.

In specific embodiments, the oral liquid suspension includes sodiumcarboxymethyl cellulose (medium viscosity, 2% aqueous solution at 25° C.400-800 cPs), present in 0.18±0.10% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumcarboxymethyl cellulose (medium viscosity, 2% aqueous solution at 25° C.400-800 cPs), present in 0.18±0.08% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumcarboxymethyl cellulose (medium viscosity, 2% aqueous solution at 25° C.400-800 cPs), present in 0.18±0.05% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumcarboxymethyl cellulose (medium viscosity, 2% aqueous solution at 25° C.400-800 cPs), present in 0.18±0.04% (w/v).

In specific embodiments, the oral liquid suspension includes sodiumcarboxymethyl cellulose (medium viscosity, 2% aqueous solution at 25° C.400-800 cPs), present in 0.18±0.02% (w/v).

In specific embodiments, the oral liquid suspension includes PROSOLV®SMCC 50M (microcrystalline cellulose and colloidal silicon dioxide),present in 1.26±0.5% (w/v).

In specific embodiments, the oral liquid suspension includes PROSOLV®SMCC 50M (microcrystalline cellulose and colloidal silicon dioxide),present in 1.26±0.4% (w/v).

In specific embodiments, the oral liquid suspension includes PROSOLV®SMCC 50M (microcrystalline cellulose and colloidal silicon dioxide),present in 1.26±0.3% (w/v).

In specific embodiments, the oral liquid suspension includes PROSOLV®SMCC 50M (microcrystalline cellulose and colloidal silicon dioxide),present in 1.26±0.2% (w/v).

In specific embodiments, the oral liquid suspension includes PROSOLV®SMCC 50M (microcrystalline cellulose and colloidal silicon dioxide),present in 1.26±0.1% (w/v).

In specific embodiments, the oral liquid suspension includes one or moreflavoring agents.

In specific embodiments, the oral liquid suspension includes theflavoring agent cherry flavor, natural & artificial.

In specific embodiments, the oral liquid suspension does not include aflavoring agent.

In specific embodiments, the oral liquid suspension includes one or morecolorants.

In specific embodiments, the oral liquid suspension includes thecolorants FD&C Red #40 and FD&C Yellow #6.

In specific embodiments, the oral liquid suspension does not include acolorant.

In specific embodiments, the oral liquid suspension includes:

Amount (% w/v) Component  2.5 ± 0.25 topiramate 0.10 ± 0.01methylparaben  0.03 ± 0.003 sodium benzoate powder  0.08 ± 0.008saccharin sodium dihydrate 3.00 ± 0.3  70% solution of sorbitol 2.25 ±0.3  propylene glycol  5 ± 0.5 glycerin (99% natural) 1.26 ± 0.15PROSOLV ® SMCC 50M (microcrystalline cellulose and colloidal silicondioxide) 0.18 ± 0.02 sodium carboxymethyl cellulose (medium viscosity,2% aqueous solution at 25° C. 400-800 cPs) 0.18 ± 0.02 xanthan gum NF0.20 ± 0.02 cherry flavor, natural & artificial  0.002 ± 0.0002 FD&C Red#40  0.0002 ± 0.00002 FD&C Yellow #6 79.67 ± 8.0  purified water  5 ±0.5 polyethylene glycol 400 0.25 ± 0.03 sodium phosphate dibasic (dried) 0.5 ± 0.05 sucralose

In specific embodiments, the oral liquid suspension has a volume of upto 50 mL.

In specific embodiments, the oral liquid suspension has a volume of upto 20 mL.

In specific embodiments, the oral liquid suspension has a volume of 0.2mL to 20 mL.

In specific embodiments, the oral liquid suspension has a volume of 0.2mL, 0.5 mL, 2.5 mL, 10 mL, 15 mL, or 20 mL.

In specific embodiments, the oral liquid suspension has a volume of 0.2mL.

In specific embodiments, the oral liquid suspension has a volume of 0.5mL.

In specific embodiments, the oral liquid suspension has a volume of 2.5mL.

In specific embodiments, the oral liquid suspension has a volume of 10mL.

In specific embodiments, the oral liquid suspension has a volume of 15mL.

In specific embodiments, the oral liquid suspension has a volume of 20mL.

In specific embodiments, the oral liquid suspension has a pH of 7.5-7.9.

In specific embodiments, the oral liquid suspension has a pH of 7.7±0.1.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 300-400 mPs.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 310-390 mPs.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 320-380 mPs.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 325-375 mPs.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 341.7±20 mPs.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 341.7±10 mPs.

In specific embodiments, the oral liquid suspension has a viscosity (at25° C.) of 341.7±5 mPs.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.3.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.25.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.2.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.05.

In specific embodiments, the oral liquid suspension has a specificgravity of not greater than 1.049.

In specific embodiments, the oral liquid suspension is packaged in acontainer.

In specific embodiments, the oral liquid suspension is packaged in anamber colored polyethylene terephthalate (PET) bottle.

In specific embodiments, the oral liquid suspension is packaged in aglass bottle.

In specific embodiments, the oral liquid suspension is packaged in ahigh density polyethylene (HDPE) bottle.

In specific embodiments, the oral liquid suspension is packaged in a lowdensity polyethylene (LDPE) bottle.

In specific embodiments, the oral liquid suspension is packaged in apolypropylene (PP) bottle.

In specific embodiments, the oral liquid suspension is packaged in aglass or plastic bottle with a child proof closure.

In specific embodiments, the oral liquid suspension is packaged in aglass or plastic bottle and the packaging further includes a syringe orcup, marked in mL, ounces, or both.

In specific embodiments, the oral liquid suspension is packaged in aglass or plastic bottle configured for use to administer multiple dosesof topiramate.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for a specified periodof time (e.g., ≥20 days, ≥30 days, ≥60 days, ≥90 days, ≥180 days, ≥12months, or ≥24 months) when tested according to <1111>USP-30 NF-25.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes Escherichia coli (E. coli).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes less than 0.1 wt. % Escherichia coli (E. coli).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes less than 0.01 wt. % Escherichia coli (E. coli).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes Burkholderia cepacia complex (BCC),

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes less than 0.1 wt. % Burkholderia cepacia complex (BCC).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for an extended periodof time encountered with the shipping and storage of the oral liquidsuspension under ambient conditions, wherein the microbial contaminationincludes less than 0.01 wt. % Burkholderia cepacia complex (BCC).

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 24 monthsunder ambient conditions.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 12 monthsunder ambient conditions.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 6 monthsunder ambient conditions.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 180 daysunder ambient conditions.

In specific embodiments, the oral liquid suspension, while packaged in acontainer, is free from microbial contamination for at least 90 daysunder ambient conditions.

In specific embodiments, the oral liquid suspension is an immediaterelease dosage form.

In specific embodiments, the oral liquid suspension exhibitsredispersibility.

In specific embodiments, the oral liquid suspension exhibitsredispersibility, such that upon turning over 3 times, the oral liquidsuspension exhibits at least 80% redispersibility.

In specific embodiments, the oral liquid suspension exhibitsredispersibility, such that upon turning over 3 times, the oral liquidsuspension exhibits at least 85% redispersibility.

In specific embodiments, the oral liquid suspension exhibitsredispersibility, such that upon turning over 3 times, the oral liquidsuspension exhibits at least 90% redispersibility.

In specific embodiments, the oral liquid suspension exhibitsredispersibility, such that upon turning over 3 times, the oral liquidsuspension exhibits at least 95% redispersibility.

In specific embodiments, the oral liquid suspension is an immediaterelease dosage form that exhibits in-vitro dissolution rate more than85% of drug release within 30 minutes, when said dosage form is placedin a dissolution vessel filled with 900 ml of 0.1N HCL, pH 1.2maintained at 37±0.5° C. and stirred at a paddle speed of 50 rpm using aUSP Type II (paddle) apparatus.

In specific embodiments, the oral liquid suspension is an immediaterelease dosage form that exhibits in-vitro dissolution rate more than88% of drug release within 30 minutes, when said dosage form is placedin a dissolution vessel filled with 900 ml of 0.1N HCL, pH 1.2maintained at 37±0.5° C. and stirred at a paddle speed of 50 rpm using aUSP Type II (paddle) apparatus.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₉₀ of not more than 200 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₉₀ of not more than 175 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₉₀ of not more than 150 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₉₀ of not more than 140 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₅₀ of not more than 100 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₅₀ of not more than 90 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₅₀ of not more than 80 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₅₀ of not more than 63 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₁₀ of not more than 30 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₁₀ of not more than 29 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₁₀ of not more than 27 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas a particle size distribution D₁₀ of not more than 26 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas the following particle size distribution:

-   -   D₉₀ of not more than 200 microns;    -   D₅₀ of not more than 100 microns; and    -   D₁₀ of not more than 30 microns.

In specific embodiments, the topiramate in the oral liquid suspensionhas the following particle size distribution:

-   -   D₉₀ of not more than 139 microns;    -   D₅₀ of not more than 64.8 microns; and    -   D₁₀ of not more than 24.65 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₉₀ of notmore than 90 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₉₀ of notmore than 80 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₉₀ of notmore than 70 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₅₀ of notmore than 50 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₅₀ of notmore than 40 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₅₀ of notmore than 30 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₁₀ of notmore than 30 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₁₀ of notmore than 20 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a particle size distribution D₁₀ of notmore than 10 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has the following particle size distribution:

-   -   D₉₀ of not more than 70 microns;    -   D₅₀ of not more than 30 microns; and    -   D₁₀ of not more than 10 microns.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension is amorphous.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension is crystalline.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a water content of not more than 1.0 wt.%.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a water content of not more than 0.75 wt.%.

In specific embodiments, the topiramate employed in the manufacture ofthe oral liquid suspension has a water content of not more than 0.5 wt.%.

In specific embodiments, the oral liquid suspension is administered to asubject that is a human.

In specific embodiments, the oral liquid suspension is administered to asubject human adult of at least 16 years in age (i.e., aged 16 years orolder).

In specific embodiments, the oral liquid suspension is administered to asubject that is a human adult of at least 18 years in age (i.e., aged 18years or older).

In specific embodiments, the oral liquid suspension is administered to asubject that is a human of less than 16 years in age.

In specific embodiments, the oral liquid suspension is administered to asubject that is a human aged 2 years or older (i.e., aged 2 years orolder).

In specific embodiments, the oral liquid suspension is administered totreat at least one of a neurological disorder and a mental disorder in asubject.

In specific embodiments, the oral liquid suspension is administered totreat a neurological disorder in a subject.

In specific embodiments, the oral liquid suspension is administered totreat a mental disorder in a subject.

In specific embodiments, the oral liquid suspension is administered totreat at least one of a neurological disorder and a mental disorder in asubject, wherein the disorder comprises at least one of (a)-(c):

-   -   (a) epilepsy—adjunctive therapy in a subject aged 2 years or        older:        -   partial-onset seizures        -   primary generalized tonic-clonic seizures        -   generalized seizures of Lennox-Gastaut syndrome    -   (b) epilepsy—monotherapy in a subject aged 16 years and older:        Conversion to monotherapy in a subject with partial-onset        seizures who are receiving treatment with carbamazepine,        phenytoin, phenobarbital, primidone, or valproate as the single        AED    -   (c) bipolar disorder: maintenance treatment of bipolar I        disorder to delay the time to occurrence of mood episodes in a        subject treated for acute mood episodes with standard therapy.

In specific embodiments, the disorder is epilepsy.

In specific embodiments, the oral liquid suspension is administered asan adjunctive therapy to a subject aged 2 years or older, to treatepilepsy.

In specific embodiments, the oral liquid suspension is administered asan adjunctive therapy to a subject aged 2 years or older, to treatpartial-onset seizures.

In specific embodiments, the oral liquid suspension is administered asan adjunctive therapy to a subject aged 2 years or older, to treatprimary generalized tonic-clonic seizures.

In specific embodiments, the oral liquid suspension is administered asan adjunctive therapy to a subject aged 2 years or older, to treatgeneralized seizures of Lennox-Gastaut syndrome.

In specific embodiments, the oral liquid suspension is administered as amonotherapy to a subject aged 16 years or older, to treat epilepsy.

In specific embodiments, the oral liquid suspension is administered as amonotherapy to a subject aged 16 years or older with partial-onsetseizures, to treat epilepsy, wherein the subject is undergoingconversion to monotherapy and is receiving treatment with carbamazepine,phenytoin, phenobarbital, primidone, or valproate as the single AED.

In specific embodiments, the oral liquid suspension is administered to asubject to treat bipolar disorder.

In specific embodiments, the oral liquid suspension is administered to asubject for maintenance treatment of bipolar I disorder, to delay thetime to occurrence of mood episodes in the subject treated for acutemood episodes with standard therapy.

In specific embodiments, the oral liquid suspension is administered,such that topiramate is administered in 25±5 mg per mL.

In specific embodiments, the oral liquid suspension is administered,such that topiramate is administered in 25±4 mg per mL.

In specific embodiments, the oral liquid suspension is administered,such that topiramate is administered in 25±3 mg per mL.

In specific embodiments, the oral liquid suspension is administered,such that topiramate is administered in 25±2.5 mg per mL.

In specific embodiments, the oral liquid suspension is administered,such that topiramate is administered in 25±1.25 mg per mL.

In specific embodiments, the oral liquid suspension is administered,such that topiramate is administered in 25 mg per mL.

In specific embodiments, the oral liquid suspension is administered,such that any one of Nos. 1-16

Volume of Amount of oral liquid topiramate No. suspension (mL) (mg) 10.1  2.5 ± 0.25 2 0.2  5 ± 0.5 3 0.4 10 ± 1.0 4 0.5 12.5 ± 1.25  5 0.615 ± 1.5 6 0.8 20 ± 2.0 7 1.0 25 ± 2.5 8 2.0 50 ± 5.0 9 2.5 62.5 ± 6.25 10 3.0 75 ± 7.5 11 4.0 100 ± 10.0 12 5.0 125 ± 12.5 13 6.0 150 ± 15.0 147.0 175 ± 17.5 15 8.0 200 ± 20.0 16 10.0 250 ± 25.0is delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that any one of Nos. 1-16

Volume of Amount of oral liquid topiramate No. suspension (mL) (mg) 10.1 2.5 2 0.2 5 3 0.4 10 4 0.5 12.5 5 0.6 15 6 0.8 20 7 1.0 25 8 2.0 509 2.5 62.5 10 3.0 75 11 4.0 100 12 5.0 125 13 6.0 150 14 7.0 175 15 8.0200 16 10.0 250is delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such 2.5±0.25 mg topiramate in 0.1 mL of the oral liquid suspension isdelivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 5.0±0.5 mg topiramate in 0.2 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 10±1.0 mg topiramate in 0.4 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 12.5±1.25 mg topiramate in 0.5 mL of the oral liquidsuspension is delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 15±1.5 mg topiramate in 0.6 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 20±2.0 mg topiramate in 0.8 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 25±2.5 mg topiramate in 1.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 50±5.0 mg topiramate in 2.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 62.5±6.25 mg topiramate in 2.5 mL of the oral liquidsuspension is delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 75±7.5 mg topiramate in 3.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 100±10 mg topiramate in 4.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 125±12.5 mg topiramate in 5.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 150±15 mg topiramate in 6.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 175±17.5 mg topiramate in 7.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 200±20 mg topiramate in 8.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 250±25 mg topiramate in 10.0 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that

-   -   2±0.2 mg topiramate in 0.2 mL of the oral liquid suspension, or    -   5±0.5 mg topiramate in 0.5 mL of the oral liquid suspension, or    -   25±2.5 mg topiramate in 2.5 mL of the oral liquid suspension, or    -   100±10.0 mg topiramate in 10 mL of the oral liquid suspension,        or    -   150±15.0 mg topiramate in 15 mL of the oral liquid suspension,        or    -   200±20.0 mg topiramate in 20 mL of the oral liquid suspension

is delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 2±0.2 mg topiramate in 0.2 mL of the oral liquid suspension isdelivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 5±0.5 mg topiramate in 0.5 mL of the oral liquid suspension isdelivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 25±2.5 mg topiramate in 2.5 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 100±10.0 mg topiramate in 10 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 150±15.0 mg topiramate in 15 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that 200±20.0 mg topiramate in 20 mL of the oral liquid suspensionis delivered to the subject.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: AUC, 0→24(micrograms per hour per ml) of 98-105.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: C_(max)(micrograms per ml) steady state of 1.5.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: T_(max)(h)of 2-3.

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: t_(1/2)(h)of 19-25 (single dose).

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including: t_(1/2)(h)of 19-25 (multiple dose).

In specific embodiments, the oral liquid suspension is administered,such that upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a pharmacokinetic (PK) profile including:

-   -   AUC, 0→24 (micrograms per ml) of 98-105;    -   Cmax (micrograms per ml) steady state of 1.5;    -   T_(max)(h) of 2-3;    -   t_(1/2)(h) of 19-25 (single dose); and    -   t_(1/2)(h) of 19-25 (multiple dose).

In specific embodiments, relative to oral tablets or chewabledispersible tablets containing an equivalent amount of topiramate,administration of the oral liquid suspension results in a lowerincidence, severity, and/or duration of adverse reactions including atleast one of dizziness, headache, diplopia, ataxia, nausea, blurredvision, somnolence, rhinitis, pharyngitis, rash, vomiting, infection,fever, accidental injury, diarrhea, abdominal pain, tremor, insomnia,somnolence, backpain, fatigue, abdominal pain, and xerostomia.

The invention will now be described with the following examples, whichdo not otherwise limit the scope of the invention as claimed.

EXAMPLES Example 1 Formulation

An oral liquid suspension containing topiramate was formulated from thefollowing substances in the amounts specified.

% W/V (mg/ml) Material/Component 2.5 topiramate 0.1 methylparaben 0.03sodium benzoate powder 0.08 saccharin sodium dihydrate powder 0.25sodium phosphate dibasic 3 sorbitol solution 70% 2.25 propylene glycol 5glycerin 99% natural grade 1.26 PROSOLV ® SMCC 50 (silicifiedmicrocrystalline cellulose) 0.18 carboxymethylcellulose sodium, mediumviscosity (2% aqueous solution at 25° C. is 400-800 cps) 0.18 xanthangum 79.67 purified water 5 polyethylene glycol 400 0.5 sucralose 0.2cherry flavor (natural and artificial) 0.002 FD&C red #40 0.0002 FD&Cyellow #6 TOTAL 100.2

Example 2 Method of Manufacturing

The oral liquid suspension containing topiramate of Example 1 wasmanufactured as follows.

Phase 1 Preparation:

-   1. Mix propylene glycol and methylparaben until completely dissolved    and homogeneous.

Phase 2 Preparation:

-   1. Mix water, sodium carboxymethyl cellulose, xanthan gun!, and    PROSOLV® SMCC 50M (microcrystalline cellulose and colloidal silicon    dioxide) until completely dissolved and homogeneous.-   2. Add sodium benzoate, sodium phosphate dibasic, and sodium    saccharin and mix until completely dissolved and homogeneous.-   3. Add polyethylene glycol; and mix until completely dissolved and    homogeneous.-   4. Add sorbitol, 70% solution and mix until completely dissolved and    homogeneous.-   5. Add topiramate and mix until completely dissolved and    homogeneous.

Phase 3 Preparation:

-   1. Add Phase 1 into Phase 2 with continuous mixing, until completely    dissolved and homogeneous.-   2. Add glycerin and mix until completely dissolved and homogeneous.-   3. Add FD&C Red #40, FD&C Yellow 46, cherry flavor, and sucralose;    and mix until completely dissolved and homogeneous.-   4. Semi-automatic fill in packaging (bottle) and manual labeling.-   5. Optionally check appearance, pH, viscosity, particle size    distribution (PSD), assay, dosage uniformity, sedimentation rate,    dissolution, deliverable volume, and/or micro testing.

Example 3 Packaging

The oral liquid suspension of Example 1 was manufactured for packaging,shipment, storage, and for use with the following.

Container Oral Dispenser Plastic bottle Measuring cup Glass bottleMeasuring syringe Measuring dropper

Example 4 Method of Administration

The oral liquid suspension of Example 1 was formulated foradministration that includes the following.

-   1. Shake well before using to ensure sufficient redispersion and    content uniformity.-   2. Measure the prescribed dose of the oral liquid suspension into    the dispenser.-   3. Orally administer the dose from the dispenser to the subject    (with or without food). The medication may be administered by the    patient, a caregiver, or a health professional.

Example 5 Test Methods 1.1 Appearance

1.1.1 Procedure

-   Pour the suspension onto a clear and shallow glass (or plastic)    dish. View over a white surface.

1.1.2 Tolerance

-   Pink suspension with shades varying with concentration. The result    is as reported.

1.2 Taste and Flavor

1.2.1 Procedure

-   Swish about 5 mL of the suspension in the mouth for about 5 seconds.

1.2.2 Tolerance

-   The suspension has a sweet cherry flavor. The result is as reported.

1.3 Water Gain or Loss

1.3.1 Procedure

-   Weigh each container at the initial testing timepoint before placing    into the stability chamber.-   Weigh the same bottle at each stability timepoint. Record    measurements until the final stability timepoint.

1.3.2 Tolerance

-   As reported.

1.4 Identification A¹

1.4.1 Reagents

Vendor/Catalog Item Reagent Description Number** 1 Ammonium Molydbate,Tetrahydrate, Spectrum/A1210 Crystal, Reagent, ACS 2 Laboratory RO WaterIn house **Or equivalent

1.4.2 Ammonium Molybdate Solution

-   Prepare a 10% (w/v) aqueous solution by dissolving 1 g of ammonium    molybdate in 10 mL of water.

1.4.3 Procedure

-   To 1 mL of the Assay Sample Solution (Section 1.13.6) add 1 mL of    the ammonium molybdate solution and mix.

1.4.4 Tolerance

-   The solution turns blue.

1.5 Identification B (USP <621>)

1.5.1 Equipment, Reagents and Procedure

-   Perform the procedure described for the Assay (Section 1.13)

1.5.2 Tolerance

-   The retention time of the major peak of the Sample solution    corresponds to that of the Standard solution, as obtained in the    Assay.

1.6 pH (USP <791>)

1.6.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 pH Meter Thermo/Orion 320PTS 047 2 pH Electrode Fisherbrand/Accumet (Catalog # PTS 32313-620-289) *Or similar calibrated/qualified equipment

1.6.2 Reagents

VENDOR/CATALOG ITEM REAGENT DESCRIPTION NUMBER** 1 Buffer Solution, pH4.00 Fisher Chemical/SB98-500 (Certified) 2 Buffer Solution, pH 7.00Fisher Chemical/SB108-500 (Certified) 3 Laboratory RO Water In house**Or equivalent

1.6.3 Procedure

-   Calibrate the pH meter using pH 4 and pH 7 buffers. Rinse the pH    electrode with laboratory RO water, then with a few portions of the    test sample. While gently stirring the sample on a magnetic stirrer,    immerse the pH electrode into the sample and record the pH value    when the measurement stabilizes. Measure in triplicate by repeating    the electrode rinsing step between each measurement.

1.6.4 Tolerance

-   3.9-4.9 (average, n=3).

1.7 Viscosity (USP <912>)

1.7.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 Rotary US Solid/USS DVT6PTS 096 Viscometer 2 Spindle US Solid/#1 or #2 sizes N/A *Or similarcalibrated/qualified equipment

1.7.2 Reagents

VENDOR/CATALOG ITEM REAGENT DESCRIPTION NUMBER** 1 Cannon ViscosityStandards Fisher Chemical/22-288-557 20 mm2/s **Or equivalent

1.7.3 Test Conditions

Temperature: 25° C. (±0.1° C.) Mode: mPa*s Spindle: #1 or #2 Spindlespeed: 60 rpm

1.7.4 Procedure

-   Equilibrate the sample to 25° C. in a 150-mL beaker. Immerse the    spindle to the recommended depth maintaining at least 1 cm clearance    from the bottom and side of the container. Use spindle #1 or #2    depending on the depth of the available suspension, and a speed of    60 rpm. Ensure that the instrument displays a stable temperature of    25° C. (±0.1° C.). Press OK and record the viscosity when the    instrument completes the measurement cycle. Perform the measurement    is triplicate by pressing RESET followed by OK between measurements.

1.7.5 Tolerance

-   As reported (average, n=3).

1.8 Specific Gravity (USP <841>)

1.8.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 Analytical A&DCompany/GH202 PTS 148 Balance *Or similar calibrated/qualified equipment

1.8.2 Reagents

ITEM REAGENT DESCRIPTION VENDOR/CATALOG NO. 1 Laboratory RO Water Inhouse **Or equivalent

1.8.3 Procedure

1. USP Method (USP <841>)

-   Select a scrupulously clean, dry pycnometer that previously has been    calibrated by determining its weight and the weight of recently    boiled water contained in it at 25° C. Adjust the temperature of the    sample to about 20° C. and fill the pycnometer with it. Adjust the    temperature of the filled pycnometer to 25° C., remove any excess    liquid, and weigh.

2. In-House Method

-   Tare a clean, dry 10-mL measuring cylinder and weigh 10 mL of    laboratory RO water at 25° C. Using a clean, dry 10-mL measuring    cylinder weigh 10 mL of the sample at 25° C. Perform the    measurements in triplicate.

1.8.4 Calculation

-   Subtract the tare weight of the pycnometer (or measuring cylinder)    from the filled weight. The specific gravity of the liquid is the    quotient obtained by dividing the weight of the sample contained in    the pycnometer (or measuring cylinder) by the weight of water    contained in it, both determined at 25° C.

1.8.5 Tolerance

-   As reported (average, n=3).

1.9 Particle Size Distribution (USP<429>)

1.9.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 Laser DiffractionMicrotrac/S3500 PTS 091 Particle Size Analyzer 2 Wet SampleMicrotrac/SDC PTS 092 Delivery System *Or similar calibrated/qualifiedequipment

1.9.2 Reagents

ITEM REAGENT DESCRIPTION VENDOR/CATALOG NO.** 1 Purified Water In house**Or equivalent

1.9.3 Instrument Settings

Dispersion Fluid: Purified Water Flow Rate: 45% Setzero Time: 30 secondsRun Time: 30 seconds Number of Runs: 4 Transparency: TransparentParticle Refractive Index: 1.59 Fluid Refractive Index: 1.33 ParticleShape: Spherical Analysis Gain: 2 Progression: Geom 8 Root Distribution:Volume Lower Edge: 0.243 μm Upper Edge: 1408 μm

1.9.4 Procedure

-   Start the flow at 45% flow rate. Select S/Z to zero the instrument.    Select LOAD and ensure that the “Transmittance” is 100%. Re-disperse    the suspension by shaking well and immediately add about 20 drops of    the suspension into the Sample Delivery Controller (SDC) using a    transfer pipette. Check the display to confirm that the particle    concentration exceeds the minimum required level. Select RUN and    record d10, d50 and d90 from the after each set of 4 runs.

1.9.5 Tolerance

-   As reported (average, n=4).

1.10 Deliverable Volume (USP <698>)

1.10.1

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 Digital Timer VWR PTS 291*Or similar calibrated/qualified equipment

1.10.2 Reagent

-   N/A

1.10.3 Procedure

-   Shake the contents of 10 containers individually. Under conditions    of use or as instructed in the labeling, carefully discharge the    contents of each container into separate dry graduated cylinders of    a rated capacity not exceeding two and a half times the volume to be    measured, and calibrated “to contain”. Care must be taken to avoid    the formation of air bubbles during the process. In the absence of    labeling instructions, support the containers at about a 30° angle    to the horizontal, and gently discharge the contents into the    graduated cylinder. Allow each container to drain for a period not    to exceed 5 s. When free from bubbles, measure the volume of each    mixture.

1.10.4 Tolerance

-   The average volume of liquid obtained from the 10 containers is NLT    100%, and the volume of each of the 10 containers lies within the    range of 95%-110% of the volume declared in the labeling. If A, the    average volume is less than 100% of that declared in the labeling,    but the volume of no container is outside the range of 95%-110%, or    if B, the average volume is NLT 100% and the volume of NMT 1    container is outside the range of 95%-110%, but within the range of    90%-115%, perform the test on 20 additional containers. The average    volume of liquid obtained from the 30 containers is NLT 100% of the    volume declared in the labeling; and the volume obtained from NMT 1    of the 30 containers is outside the range of 95%-110%, but within    the range of 90%-115% of the volume declared on the labeling.

1.11 Sedimentation Rate

1.11.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 Digital Timer VWR PTS 291*Or similar calibrated/qualified equipment

1.11.2 Procedure

-   Shake the suspension well for two minutes to re-disperse. Pour 50 or    100 mL of the sample into a 100-mL measuring cylinder and start the    timer. Securely seal the measuring cylinder with parafilm to prevent    water loss. Measure and record the amount of sediment after 10    minutes, 1 hour, 1½ hours, 2 hours and 24 hours.

1.11.3 Tolerance

-   As reported.

1.12 Assessment of Re-Dispersibility

1.12.1 Procedure

-   Perform the procedure described in section 3.10: SEDIMENTATION RATE.    After 24 hours, invert the measuring cylinder through 180°. Return    to the upright position. Repeat the inversions until the suspension    is uniformly distributed. Record the number of inversions required    to restore uniformity.

1.12.2 Calculation

-   If uniformity is attained in one inversion, the suspension has 100%    ease of re-dispersibility. Every additional inversion decreases the    ease of re-dispersibility by 5%.

1.12.3 Tolerance

-   NLT 50%

1.13 Assay (<621>)

1.13.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 HPLC System Waters/2695Separation PTS 069 or Module PTS 070 2 Detector Waters/2410 RefractivePTS 072 Index Detector 3 Analytical A&D Company/GH202 PTS 148 Balance 4Ultrasonic Branson/2210R-DTH PTS 262 Cleaner 5 Wrist-ActionBurrell/Model 75 CLL018 Shaker *Or similar calibrated/qualifiedequipment

1.13.2 Reagents and Standards

VENDOR/CATALOG ITEM EQUIPMENT NUMBER** 1 Acetonitrile, HPLC GradeSpectrum/HP419 2 Laboratory RO Water In house 3 USP Topiramate RSUSP/1672206 4 USP Topiramate related USP/1672210 compound A RS 5 USPFructose RS USP/1286504 **Or equivalent

1.13.3 Chromatographic Conditions

Flow Rate: 0.6 mL/min Column: Phenomenex Luna ® Omega 5 μm PS C18 100 Å,250 × 4.6 mm, (Catalog Number 00G-4753-E0) or equivalent. ColumnTemperature: 50° C. Detector Temperature: 50° C. Mobile Phase:Acetonitrile and water (50:50) Injection Volume: 20 μL Retention Time:Approx. 7 minutes Run Time: 15 minutes

-   Note: The Mobile Phase and all solutions must be prepared fresh    prior to analysis.

1.13.4 Mobile Phase

-   Add 500 mL of acetonitrile to 500 mL of RO water and mix thoroughly.    Pass the solution through a nylon filter of 0.45 μm pore size and    degas by sonicating for 15 minutes.

1.13.5 Standard Solution

-   Accurately weigh and transfer about 50 mg of USP Topiramate RS to a    10-mL volumetric flask. Dissolve in 7 mL of Mobile Phase by shaking    for 30 minutes, using a wrist-action shaker, and sonicating for 5    minutes. Allow the solution to cool to room temperature and dilute    to volume with Mobile Phase. Prepare standards in duplicate    (Standard A and B) and pass each standard through a fresh PTFE    filter of 0.45 μm pore size.

1.13.6 Sample Solution

-   Re-disperse the suspension by shaking the sample bottle well. Tare a    5-mL volumetric flask. Transfer and weigh about 1 mL of the    suspension into the volumetric flask. Dissolve in 3 mL of Mobile    Phase by shaking for 30 minutes, using a wrist-action shaker, and    sonicating for 5 minutes. Allow the solution to cool to room    temperature and dilute to volume with Mobile Phase, Prepare samples    in triplicate and pass each sample solution through a fresh PTFE    filter of 0.45 μm pore size.

1.13.7 System Suitability Solution

-   Accurately weigh and transfer about 1 mg each of USP Topiramate    Related Compound A RS and USP Fructose RS to a volumetric flask.    Dissolve in 3 mL of Standard Solution by shaking for 30 minutes,    using a wrist-action shaker, and sonicating for 5 minutes. Allow the    solution to cool to room temperature and dilute to volume with    Standard Solution. Pass the solution through a PTFE filter of 0.45    μm pore size.

1.13.8 Injection Format

-   Start with duplicate Blank injections of the Mobile Phase. Inject    Standards A and B in duplicate to check the accuracy of the Standard    Solution Preparation (Section 3.13.9.1). If the standard check    passes, inject the System Suitability Solution in duplicate and    perform six injections of Standard A (Section 3.13.9.2). If the    system suitability test passes, inject samples by alternating    between duplicate injections of Standard A followed by no more than    four injections of the samples. The run should end with duplicate    injections of Standard A.

1.13.9 Calculations

1.13.9.1 Standard Check

-   The accuracy of the Standard Solution Preparation should be checked    by comparing the Relative Response Factor (RRF) for topiramate of    each standard. The Standard Solution Preparations are not valid for    the analysis unless the result of the comparison meets the    specifications listed below:

$\begin{matrix}{{RRF}_{a} = \frac{{Conc}_{a}}{{Resp}_{a}}} \\{{RRF}_{b} = \frac{{Conc}_{b}}{{Resp}_{b}}} \\{{Result} = {\frac{{RRF}_{a}}{{RRF}_{b}}100}} \\{98.00 \leq {Result} \leq 102.00}\end{matrix}$

-   Where: Resp_(a)=The absorbance response of Standard A-   Resp_(b)=The absorbance response of Standard B-   Conc_(a)=The concentration of Standard A-   Conc_(b)=The concentration of Standard B-   Result=The ratio of the response factors expressed as a percent

1.13.9.2 System Suitability

-   Check the relative retention times for fructose, topiramate related    compound A and topiramate. Check the resolution between topiramate    related compound A and topiramate. Check the tailing factor and    calculate the relative standard deviation of the topiramate peak    area from Standard A. The HPLC system is valid if it meets the    following specifications:    -   1. Relative retention times: Fructose (0.45), Topiramate related        compound A (0.90), Topiramate (1.0).    -   2. Resolution: NLT 1.5 between topiramate related compound A and        topiramate, System suitability solution. Tailing factor: NMT 2.0    -   3. Relative standard deviation: NMT 2.0%

1.13.9.3 Sample Recovery

-   Calculate the amount of topiramate in each sample solution as    follows:

${{Amount}\mspace{14mu} {of}\mspace{14mu} {topiramate}\mspace{14mu} (\%)} = \frac{{Area}_{spl} \times {Conc}_{std} \times {Vol}_{spl} \times 100}{{Area}_{std} \times {Conc}_{batch} \times {Mass}_{spl}}$

-   Where:-   Area_(spl)=Area of topiramate peak from sample solution-   Area_(std)=Area of topiramate peak in standard solution-   Cone_(std)=Theoretical standard concentration (in mg/mL)-   Cone_(batch)=Theoretical batch concentration (in mg/mg)-   Vol_(spl)=Sample Volume (5 mL)-   Mass_(spl)=Sample Mass (mg)

1.13.9.4 Calculation Not

-   Many Chromatography systems and integrators will perform some or all    of the calculations automatically. These systems should be spot    checked manually to determine that they perform calculations as    expected.

1.13.10 Tolerance

-   Topiramate oral suspension contains NLT 90.0% and NMT 110.0% of the    labeled amounts of topiramate (C₁₂H₂₁NO₈S).

1.14 Content Uniformity (USP <905>)

1.14.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 HPLC System Waters/2695Separation PTS 069 or Module PTS 070 2 Detector Waters/2410 RefractivePTS 072 Index Detector 3 Analytical A&D Company/GH202 PTS 148 Balance 4Ultrasonic Branson/2210R-DTH PTS 262 Cleaner 5 Wrist-ActionBurrell/Model 75 CLL018 Shaker *Or similar calibrated/qualifiedequipment

1.14.2 Reagents and Standards

VENDOR/CATALOG ITEM EQUIPMENT NUMBER** 1 Acetonitrile, HPLC GradeSpectrum/HP419 2 Laboratory RO Water In house 3 USP Topiramate RSUSP/1672206 4 USP Topiramate related USP/1672210 compound A RS 5 USPFructose RS USP/1286504 **Or equivalent

1.14.3 Chromatographic Conditions

Flow Rate: 0.6 mL/min Column: Phenomenex Luna ® Omega 5 μm PS C18 100 Å,250 × 4.6 mm, (Catalog Number 00G-4753-E0) or equivalent. ColumnTemperature: 50° C. Detector Temperature: 50° C. Mobile Phase:Acetonitrile and water (50:50) Injection Volume: 20 μL Retention Time:Approx. 7 minutes Run Time: 15 minutes

-   Note: The Mobile Phase and all solutions must be prepared fresh    prior to analysis.

1.14.2 Mobile Phase

-   Add 500 mL of acetonitrile to 500 mL of RO water and mix thoroughly.    Pass the solution through a nylon filter of 0.45 μm pore size and    degas by sonicating for 5 minutes.

1.14.3 Standard Solution

-   Accurately weigh and transfer about 50 mg of USP Topiramate RS to a    10-mL volumetric flask. Dissolve in 7 mL of Mobile Phase by shaking    for 30 minutes, using a wrist-action shaker, and sonicating for 5    minutes. Allow the solution to cool to room temperature and dilute    to volume with Mobile Phase. Prepare standards in duplicate    (Standard A and B) and pass each standard through a fresh PTFE    filter of 0.45 μm pore size.

1.14.4 Sample Solution

-   Re-disperse the suspension by shaking the sample bottle well. Tare    three 5-mL volumetric flasks. Transfer and weigh about 1 mL of the    suspension from three locations, near the top, middle and bottom,    respectively, of the container into each volumetric flask. Dissolve    in 3 mL of Mobile Phase by shaking for 30 minutes, using a wrist    action shaker, and sonicating for 5 minutes. Allow each solution to    cool to room temperature and dilute to volume with Mobile Phase.    Pass each sample solution through a fresh PTFE filter of 0.45 μm    pore size.

1.14.5 System Suitability Solution

-   Accurately weigh and transfer about 1 mg each of USP Topiramate    Related Compound A RS and USP Fructose RS to a 5-mL volumetric    flask. Dissolve in 3 mL of Standard Solution by shaking for 30    minutes, using a wrist-action shaker, and sonicating for 5 minutes.    Allow the solution to cool to room temperature and dilute to volume    with Standard Solution. Pass the solution through a PTFE filter of    0.45 μm pore size.

1.14.6 Injection Format

-   Start with duplicate Blank injections of the Mobile Phase. Inject    Standards A and B in duplicate to check the accuracy of the Standard    Solution Preparation (Section 1.14.7.1). If the standard check    passes, inject the System Suitability Solution in duplicate and    perform six injections of Standard A (Section 1.14.7.2). If the    system suitability test passes, inject samples by alternating    between duplicate injections of Standard A followed by no more than    four injections of the samples. The run should end with duplicate    injections of Standard A.

1.14.7 Calculations

1.14.7.1 Standard Check

-   The accuracy of the Standard Solution Preparation should be checked    by comparing the Relative Response Factor (RRF) for topiramate of    each standard. The Standard Solution Preparations are not valid for    the analysis unless the result of the comparison meets the    specifications listed below:

$\begin{matrix}{{RRF}_{a} = \frac{{Conc}_{a}}{{Resp}_{a}}} \\{{RRF}_{b} = \frac{{Conc}_{b}}{{Resp}_{b}}} \\{{Result} = {\frac{{RRF}_{a}}{{RRF}_{b}}100}} \\{98.00 \leq {Result} \leq 102.00} \\{{{{Where}\text{:}\mspace{14mu} {Resp}_{a}} \equiv {{The}\mspace{14mu} {absorbance}\mspace{14mu} {response}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} A}}\mspace{284mu}} \\{{{Resp}_{b} \equiv {{The}\mspace{14mu} {absorbance}\mspace{14mu} {response}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} B}}\mspace{194mu}} \\{{{Conc}_{a} \equiv {{The}\mspace{14mu} {concentration}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} A}}\mspace{275mu}} \\{{{Conc}_{b} \equiv {{The}\mspace{14mu} {concentration}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} B}}\mspace{275mu}} \\{{{Result} \equiv {{The}\mspace{14mu} {ratio}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {response}\mspace{14mu} {factors}\mspace{14mu} {expressed}\mspace{14mu} {as}\mspace{14mu} a\mspace{14mu} {percent}}}\mspace{20mu}}\end{matrix}$

1.14.7.2 System Suitability

-   Check the relative retention times for fructose, topiramate related    compound A and topiramate. Check the resolution between topiramate    related compound A and topiramate. Check the tailing factor and    calculate the relative standard deviation of the topiramate peak    area from Standard A. The HPLC system is valid if it meets the    following specifications:    -   1. Relative retention times: Fructose (0.45), Topiramate related        compound A (0.90), Topiramate (1.0).    -   2. Resolution: NLT 1.5 between topiramate related compound A and        topiramate, System suitability solution. Tailing factor: NMT        2.0.    -   3. Relative standard deviation: NMT 2.0%.

1.14.7.3 Delivered Dose

-   Calculate the amount of topiramate in each sample solution as    follows:

$\begin{matrix}{{{Amount}\mspace{14mu} {of}\mspace{14mu} {topiramate}\mspace{14mu} (\%)} = \frac{{Area}_{spl} \times {Conc}_{std} \times {Vol}_{spl} \times 100}{{Area}_{std} \times {Conc}_{batch} \times {Mass}_{spl}}} \\{{{Where}\text{:}}\mspace{945mu}} \\{{{Area}_{spl} = {{Area}\mspace{14mu} {of}\mspace{14mu} {topiramate}\mspace{14mu} {peak}\mspace{14mu} {from}\mspace{14mu} {sample}\mspace{14mu} {solution}}}\mspace{394mu}} \\{{{Area}_{std} = {{Area}\mspace{14mu} {of}\mspace{14mu} {topiramate}\mspace{14mu} {peak}\mspace{14mu} {in}\mspace{14mu} {standard}\mspace{14mu} {solution}}}\mspace{416mu}} \\{{{Conc}_{std} = {{Theoretical}\mspace{14mu} {standard}\mspace{14mu} {concentration}\mspace{14mu} \left( {{in}\mspace{14mu} {mg}\text{/}{mL}} \right)}}\mspace{394mu}} \\{{{Conc}_{batch} = {{Theoretical}\mspace{14mu} {batch}\mspace{14mu} {concentration}\mspace{14mu} \left( {{in}\mspace{14mu} {mg}\text{/}{mg}} \right)}}\mspace{410mu}} \\{{{Vol}_{spl} = {{Sample}\mspace{14mu} {Volume}\mspace{14mu} \left( {5\mspace{14mu} {mL}} \right)}}\mspace{664mu}} \\{{{Mass}_{spl} = {{Sample}\mspace{14mu} {Mass}\mspace{14mu} ({mg})}}\mspace{700mu}} \\{{Calculate}\mspace{14mu} {the}\mspace{14mu} {Sample}\mspace{14mu} {standard}\mspace{14mu} {deviation}\mspace{14mu} \left( {n = 10} \right)\mspace{14mu} {and}\mspace{14mu} {the}\mspace{14mu} {Acceptance}\mspace{14mu} {Value}\mspace{14mu} {by}\mspace{14mu} {the}\mspace{14mu} {formula}\text{:}} \\{{{M - X}} + {ks}} \\{{{{{Where}\text{:}\mspace{14mu} M} = {{According}\mspace{14mu} {to}\mspace{14mu} X}},{{{as}\mspace{14mu} {described}\mspace{14mu} {in}\mspace{14mu} {Table}\mspace{14mu} 2\mspace{14mu} {of}\mspace{14mu} {USP}}\mspace{14mu} < 905 >}}\mspace{225mu}} \\{{X = {{Mean}\mspace{14mu} {of}\mspace{14mu} {individual}\mspace{14mu} {contents}\mspace{14mu} {Found}}}\mspace{394mu}} \\{{k = {{Acceptability}\mspace{14mu} {constant}\mspace{14mu} \left( {{k = 2.4},{{{for}\mspace{14mu} n} = 10}} \right)}}\mspace{304mu}}\end{matrix}$

S—sample standard deviation

1.14.7.4 Calculation Notes

-   Many Chromatography systems and integrators will perform some or all    of the calculations automatically. These systems should be spot    checked manually to determine that they perform calculations as    expected.

1.14.8 Tolerance

-   The acceptance value of the first 10 dosage units is less than or    equal to L1%. If the acceptance value is >L1%, test the next 20    units, and calculate the acceptance value. The requirements are met    if the final acceptance value of the 30 dosage units is ≤L1%, and no    individual content of any dosage unit is less than [1−(0.01)(L2)]M    nor more than [1+(0.01)(L2)]M as specified in the Calculation of    Acceptance Value under Content Uniformity in USP <905>. L1 is 15.0    and L2 is 25.0.

1.15 Chromatographic Purity (USP <621>)

1.15.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 HPLC System Waters/2695Separation PTS 069 or Module PTS 070 2 Detector Waters/2410 RefractivePTS 072 Index Detector 3 Analytical A&D Company/GH202 PTS 148 Balance 4Ultrasonic Branson/2210R-DTH PTS 262 Cleaner 5 Wrist-ActionBurrell/Model 75 CLL018 Shaker *Or similar calibrated/qualifiedequipment

1.15.2 Reagents and Standards

VENDOR/CATALOG ITEM EQUIPMENT NUMBER** 1 Acetonitrile, HPLC GradeSpectrum/HP419 2 Laboratory RO Water In house 3 USP Topiramate RSUSP/1672206 4 USP Topiramate related USP/1672210 compound A RS 5 USPFructose RS USP/1286504 **Or equivalent

1.15.3 Chromatographic Conditions

Flow Rate: 0.6 mL/min Column: Phenomenex Luna ® Omega 5 μm PS C18 100 Å,250 × 4.6 mm, (Catalog Number 00G-4753-E0) or equivalent. ColumnTemperature: 50° C. Detector Temperature: 50° C. Mobile Phase:Acetonitrile and water (50:50) Injection Volume: 20 μL Retention Time:Approx. 7 minutes Run Time: 15 minutes

-   Note: The Mobile Phase and all solutions must be prepared fresh    prior to analysis.

3.15.4 Mobile Phase

-   Add 500 mL of acetonitrile to 500 mL of RO water and mix thoroughly.    Pass the solution through a nylon filter of-   0.45 μm pore size and degas by sonicating for 5 minutes.

1.15.5 Standard Solution

-   Accurately weigh and transfer about 50 mg of USP Topiramate RS to a    10-mL volumetric flask. Dissolve in 7 mL of Mobile Phase by shaking    for 30 minutes, using a wrist-action shaker, and sonicating for 5    minutes. Allow the solution to cool to room temperature and dilute    to volume with Mobile Phase. Prepare standards in duplicate    (Standard A and B) and pass each standard through a fresh PTFE    filter of 0.45 μm pore size.

1.15.6 Sample Solution

-   Re-disperse the suspension by shaking the sample bottle well.    Transfer about 2.5 mL of the suspension into the volumetric flask.    Dissolve in 1 mL of Mobile Phase by shaking for 30 minutes, using a    wrist-action shaker, and sonicating for 5 minutes. Allow the    solution to cool to room temperature and dilute to volume with    Mobile Phase. Prepare samples in triplicate and pass each sample    solution through a fresh PTFE filter of 0.45 μm pore size.

1.15.7 System Suitability Solution

-   Accurately weigh and transfer about 1 mg each of USP Topiramate    Related Compound A RS and USP Fructose RS to a 5-mL volumetric    flask. Dissolve in 3 mL of Standard Solution by shaking for 30    minutes, using a wrist-action shaker, and sonicating for 5 minutes.    Allow the solution to cool to room temperature and dilute to volume    with Standard Solution. Pass the solution through a PTFE filter of    0.45 μm pore size.

1.15.8 Injection Format

-   Start with duplicate Blank injections of the Mobile Phase. Inject    Standards A and B in duplicate to check the accuracy of the Standard    Solution Preparation (Section 1.15.9.1). If the standard check    passes, inject the System Suitability Solution in duplicate and    perform six injections of Standard A (Section 1.15.9.2). If the    system suitability test passes, inject samples by alternating    between duplicate injections of Standard A followed by no more than    four injections of the samples. The run should end with duplicate    injections of Standard A.

1.15.9 Calculations

1.15.9.1 Standard Check

-   The accuracy of the Standard Solution Preparation should be checked    by comparing the Relative Response Factor (RRF) for topiramate of    each standard. The Standard Solution Preparations are not valid for    the analysis unless the result of the comparison meets the    specifications listed below:

$\begin{matrix}{{RRF}_{a} = \frac{{Conc}_{a}}{{Resp}_{a}}} \\{{RRF}_{b} = \frac{{Conc}_{b}}{{Resp}_{b}}} \\{{Result} = {\frac{{RRF}_{a}}{{RRF}_{b}}100}} \\{98.00 \leq {Result} \leq 102.00} \\{{{{Where}\text{:}\mspace{14mu} {Resp}_{a}} \equiv {{The}\mspace{14mu} {absorbance}\mspace{14mu} {response}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} A}}\mspace{284mu}} \\{{{Resp}_{b} \equiv {{The}\mspace{14mu} {absorbance}\mspace{14mu} {response}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} B}}\mspace{194mu}} \\{{{Conc}_{a} \equiv {{The}\mspace{14mu} {concentration}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} A}}\mspace{275mu}} \\{{{Conc}_{b} \equiv {{The}\mspace{14mu} {concentration}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} B}}\mspace{275mu}} \\{{{Result} \equiv {{The}\mspace{14mu} {ratio}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {response}\mspace{14mu} {factors}\mspace{14mu} {expressed}\mspace{14mu} {as}\mspace{14mu} a\mspace{14mu} {percent}}}\mspace{20mu}}\end{matrix}$

1.15.9.2 System Suitability

-   Check the relative retention times for fructose, topiramate related    compound A and topiramate.-   Check the resolution between topiramate related compound A and    topiramate. Check the tailing factor and calculate the relative    standard deviation of the topiramate peak area from Standard A. The    HPLC system is valid if it meets the following specifications:    -   1. Relative retention times: Fructose (0.45), Topiramate related        compound A (0.90), Topiramate (1.0).    -   2. Resolution: NLT 1.5 between topiramate related compound A and        topiramate, System suitability solution.    -   3. Tailing factor: NMT 2.0.    -   4. Relative standard deviation: NMT 2.0%.

1.15.9.3 Sample Recovery

-   Calculate the amount of topiramate in each sample solution as    follows:

${{Amount}\mspace{14mu} {of}\mspace{14mu} {topiramate}\mspace{14mu} (\%)} = \frac{{Area}_{spl} \times {Conc}_{std} \times {Vol}_{spl} \times 100}{{Area}_{std} \times {Conc}_{batch} \times {Mass}_{spl}}$

Where:

-   -   Area_(spl)=Area of topiramate peak from sample solution    -   Area_(std)=Area of topiramate peak in standard solution    -   Conc_(std)=Theoretical standard concentration (in mg/mL)    -   Conc_(batch)=Theoretical batch concentration (in mg/mg)    -   Vol_(spl)=Sample Volume (5 mL)    -   Mass_(spl)=Sample Mass (mg)

1.15.9.4 Calculation Notes

-   Many Chromatography systems and integrators will perform some or all    of the calculations automatically. These systems should be spot    checked manually to determine that they perform calculations as    expected.

1.15.10 Tolerance

-   Topiramate oral suspension contains NLT 90.0% and NMT 110.0% of the    labeled amounts of topiramate (C₁₂H₂₁NO₈S).

1.16 Related Compounds (USP <621>)

1.16.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 HPLC System Waters/2695Separation PTS 069 or Module PTS 070 2 Detector Waters/2410 RefractivePTS 072 Index Detector 3 Analytical A&D Company/GH202 PTS 148 Balance 4Ultrasonic Branson/2210R-DTH PTS 262 Cleaner 5 Wrist-ActionBurrell/Model 75 CLL018 Shaker *Or similar calibrated/qualifiedequipment

1.16.2 Reagents and Standards

VENDOR/CATALOG ITEM EQUIPMENT NUMBER** 1 Acetonitrile, HPLC GradeSpectrum/HP419 2 Laboratory RO Water In house 3 USP Topiramate RSUSP/1672206 4 USP Topiramate related USP/1672210 compound A RS **Orequivalent

1.16.3 Chromatographic Conditions

Flow Rate: 0.6 mL/min Column: Phenomenex Luna ® Omega 5 μm PS C18 100 Å,250 × 4.6 mm, (Catalog Number 00G-4753-E0) or equivalent. ColumnTemperature: 50° C. Detector Temperature: 50° C. Mobile Phase:Acetonitrile and water (50:50) Injection Volume: 50 μL Retention Time:Approx. 7 minutes Run Time: 40 minutes (or NLT 5 times the retentiontime of topiramate)

-   Note: The Mobile Phase and all solutions must be prepared fresh    prior to analysis.

1.16.4 Mobile Phase

-   Add 500 mL of acetonitrile to 500 mL of RO water and mix thoroughly.    Pass the solution through a nylon filter of 0.45 μm pore size.

1.16.5 Standard Solution

-   Accurately weigh and transfer about 12 mg of USP Topiramate RS and 6    mg of USP Topiramate Related Compound A RS to a 10-mL volumetric    flask. Dissolve in 7 mL of Mobile Phase by shaking for 30 minutes,    using a wrist action shaker, and sonicating for 5 minutes. Allow the    solution to cool to room temperature and dilute to volume with    Mobile Phase. Pass the standard solution through a fresh PTFE filter    of 0.45 μm pore size.

1.16.6 Peak Identification Solution

-   Accurately weigh and transfer about 6 mg of USP Topiramate RS and 6    mg of USP Topiramate Related Compound A RS to a 10-mL volumetric    flask. Dissolve in 7 mL of Mobile Phase by shaking for 30 minutes,    using a wrist action shaker, and sonicating for 5 minutes. Allow the    solution to cool to room temperature and dilute to volume with    Mobile Phase. Pass the standard solution through a fresh PTFE filter    of 0.45 μm pore size.

1.16.7 Sample Solution

-   Re-disperse the suspension by shaking the sample bottle well. Tare a    5-mL volumetric flask. Transfer and weigh about 1 mL of the    suspension into the volumetric flask. Dissolve in 3 mL of Mobile    Phase by shaking for 30 minutes, using a wrist-action shaker, and    sonicating for 5 minutes. Allow the solution to cool to room    temperature and dilute to volume with Mobile Phase. Pass each sample    solution through a fresh PTFE filter of 0.45 μm pore size.

1.16.8 Injection Format

-   Start with duplicate Blank injections of the Mobile Phase. Inject    the Peak Identification Solution in duplicate and perform six    injections of the Standard Solution (Section 1.16.9.1). If the    system suitability test passes, inject samples by alternating    between duplicate injections of the Standard Solution followed by no    more than four injections of the samples. The run should end with    duplicate injections of the Standard Solution.

1.16.9 Calculations

1.16.9.1 System Suitability

-   Identify the peaks due to topiramate related compound A and    topiramate using the relative retention times. Calculate the    relative standard deviation and of the topiramate peak area from    Standard A. The HPLC system is valid if it meets the following    specifications:    -   1. Relative retention times: Topiramate related compound A        (0.66), Topiramate (1.0)    -   2. Relative standard deviation: NMT 5.0%

1.16.9.2 Sample Recovery

-   Calculate the percentage of each impurity in the portion of    Suspension taken:

Result=(r _(U) /r _(S))×(C _(S) /C _(U))×(1/F)×100

Where:

-   -   r_(U)=peak response for the individual impurity from the Sample        solution    -   r_(S)=peak response of topiramate from the Standard solution    -   C_(S)=concentration of USP Topiramate RS in the Standard        solution (mg/mL)    -   C_(U)=nominal concentration of topiramate in the Sample solution        (mg/mL)    -   F=relative response factor

1.16.9.3 Calculation Notes

-   Many Chromatography systems and integrators will perform some or all    of the calculations automatically. These systems should be spot    checked manually to determine that they perform calculations as    expected.

1.16.10 Tolerance

-   Topiramate related compound A: NMT 0.5%-   Individual unspecified degradation product: NMT 0.2%-   Total impurities: NMT 0.7%

1.17 Dissolution (USP <711>)

1.17.1 Equipment

ITEM EQUIPMENT MANUFACTURER/MODEL* ASSET # 1 HPLC System Waters/2695Separation PTS 069 or Module PTS 070 2 Detector Waters/2410 RefractivePTS 072 Index Detector 3 Analytical A&D Company/GH202 PTS 148 Balance 4Ultrasonic Branson/2210R-DTH PTS 262 Cleaner 5 Wrist-ActionBurrell/Model 75 CLL018 Shaker *Or similar calibrated/qualifiedequipment

1.17.2 Reagents and Standards

VENDOR/CATALOG ITEM EQUIPMENT NUMBER** 1 Acetonitrile, HPLC GradeSpectrum/HP419 2 Laboratory RO Water In house 3 USP Topiramate RSUSP/1672206 **Or equivalent

1.17.3 Dissolution Conditions

Apparatus: Apparatus 2 (Paddles) Dissolution Medium: Purified Water(degassed) Volume: 900 mL Revolutions per minute: 50 rpm Temperature:37° C. + 0.5° C. Cannula Tip Filters: Hanson 45 μm (QLA LLC. Catalognumber FIL045-HR-1000) Sampling times: 5, 10, 20, 30 and 40 minutesMinimum number of 6 units (12 units for clinical units to test: testingproduct) Sample Volume: 10 mL at each time point

1.17.4 Chromatographic Conditions

Flow Rate: 1.0 mL/min Column: Phenomenex Luna ® Omega 5 μm PS C18 100 Å,250 × 4.6 mm, (Catalog Number 00G-4753-E0) or equivalent. ColumnTemperature: 30° C. Detector Temperature: 50° C. Mobile Phase:Acetonitrile and water (1:1) Injection Volume: 100 μL Retention Time:Approx. 8 minutes Run Time: 15 minutes

1.17.5 Dissolution Medium

-   Warm purified water to about 40° C., degas and dispense 900 mL of    medium directly into each dissolution vessels. Equilibrate the media    to the bath temperature. Measure and record media temperatures in    each vessel immediately before adding the sample.

1.17.6 Mobile Phase

-   Mix 500 mL of RO water and 500 mL of acetonitrile in a 1000-mL    beaker. Mix well and filter through a 0.45 μm nylon filter and degas    by sonicating for 15 minutes.

1.17. 7 Standard Solution Preparation

-   Accurately weigh and transfer about 10 mg of USP Topiramate RS, to a    100-mL volumetric flask. Dissolve in 70 mL of Dissolution Medium by    shaking for 30 minutes, using a wrist action shaker, and sonicating    for 5 minutes. Allow the solution to cool to room temperature and    dilute to volume with Dissolution Medium. Prepare in duplicate to    make Standard A and Standard B. Filter each sample using a fresh    0.45 μm filter before HPLC analysis.

1.17.8 Sample Preparation

-   Shake the Topiramate suspension thoroughly. Accurately weigh about 4    mL of the suspension in 5-mL luer-lock syringes and carefully    transfer the entire volume into the center-bottom of each    dissolution vessel. Avoid agitating the suspension during transfer.    Start the dissolution run immediately after all samples have been    loaded. At the specified sampling time, manually sample 10 mL of    dissolution media through 45 μm cannula-tip filters. Pass each    sample through fresh PTFE filters of 0.45 μm pore size before HPLC    analysis.

1.17.9 Injection Format

-   Start with duplicate injections of Dissolution Media. Perform    duplicate injections of Standard A and Standard B to check standard    preparation (Section 1.17.10.1). If the standard check passes,    proceed with at least six injections of Standard A to determine    system suitability (Section 1.17.10.2). If the system suitability    test passes, test the samples by alternating between two injections    of Standard A followed by no more than twelve injections of the    samples. The run should end with duplicate injections of Standard A.

1.17.10 Calculations

1.17.10.1 Standard Check

-   The accuracy of the Standard Solution should be checked by comparing    the Relative Response Factor (RRF) for Topiramate of each standard.    The Standard Solution are not valid for the analysis unless the    result of the comparison meets the specifications listed below:

$\begin{matrix}{{RRF}_{a} = \frac{{Conc}_{a}}{{Resp}_{a}}} \\{{RRF}_{b} = \frac{{Conc}_{b}}{{Resp}_{b}}} \\{{Result} = {\frac{{RRF}_{a}}{{RRF}_{b}}100}} \\{98.00 \leq {Result} \leq 102.00} \\{{{{Where}\text{:}\mspace{14mu} {Resp}_{a}} \equiv {{The}\mspace{14mu} {absorbance}\mspace{14mu} {response}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} A}}\mspace{284mu}} \\{{{Resp}_{b} \equiv {{The}\mspace{14mu} {absorbance}\mspace{14mu} {response}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} B}}\mspace{194mu}} \\{{{Conc}_{a} \equiv {{The}\mspace{14mu} {concentration}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} A}}\mspace{275mu}} \\{{{Conc}_{b} \equiv {{The}\mspace{14mu} {concentration}\mspace{14mu} {of}\mspace{14mu} {Standard}\mspace{14mu} B}}\mspace{275mu}} \\{{{Result} \equiv {{The}\mspace{14mu} {ratio}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {response}\mspace{14mu} {factors}\mspace{14mu} {expressed}\mspace{14mu} {as}\mspace{14mu} a\mspace{14mu} {percent}}}\mspace{14mu}}\end{matrix}$

1.17.10.2 System Suitability Check

-   Calculate relative standard deviation of topiramate peak area for    six injections of the Standard Solution. The HPLC system is valid if    it meets the following specifications:    -   1. Column Efficiency: NLT 5000 theoretical plates    -   2. Tailing Factor: NMT 2.0    -   3. % RSD: NMT 2.0%    -   4. Where % RSD=Relative Standard Deviation of Standard Solution        peak Area

1.17.10.3 Percent Dissolved

-   Calculate the amount of Topiramate recovered at each sample time    point. Calculate the average, the standard deviation and the    relative standard deviation. The found value for each sample should    be calculated as follows:

$\begin{matrix}{{RRF} = \frac{{Conc}_{std}}{{Area}_{std}}} \\{{Conc}_{spl} = {{Area}_{spl}{RRF}}} \\{{removed}_{{sampl},} = {{Conc}_{spl}{Volume}_{spl}}} \\{{Found} = {100\left( {\left( {{Conc}_{spl}{Scalar}} \right) + {removed}_{prev}} \right)\text{/}{Label}}} \\{{{{Where}\text{:}\mspace{14mu} {Found}} = {{Amount}\mspace{14mu} {dissolved}\mspace{14mu} {found}\mspace{14mu} {in}\mspace{14mu} {sample}\mspace{14mu} {expressed}\mspace{14mu} {as}\mspace{14mu} a\mspace{14mu} {percent}}}\mspace{194mu}} \\{{{Conc}_{spl} = {{Found}\mspace{14mu} {concentration}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {sample}\mspace{14mu} {in}\mspace{14mu} {mg}\text{/}{mL}}}\mspace{236mu}} \\{{{Area}_{spl} = {{Area}\mspace{14mu} {found}\mspace{14mu} {for}\mspace{14mu} {the}\mspace{14mu} {sample}}}} \\{{{Area}_{std} = {{Area}\mspace{14mu} {found}\mspace{14mu} {for}\mspace{14mu} {the}\mspace{14mu} {standard}}}\mspace{436mu}} \\{{{Conc}_{std} = {{Theoretical}\mspace{14mu} {concentration}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {standard}\mspace{14mu} {in}\mspace{14mu} {mg}\text{/}{mL}}}\mspace{169mu}} \\{{{RRF} = {{Relative}\mspace{14mu} {response}\mspace{14mu} {factor}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {standard}}}\mspace{326mu}} \\{{{Removed}_{spl} = {{The}\mspace{14mu} {amount}\mspace{14mu} {of}\mspace{14mu} {material}\mspace{14mu} {removed}\mspace{14mu} {during}\mspace{14mu} {sampling}\mspace{14mu} ({mg})}}} \\{{{Removed}_{prev} = {{The}\mspace{14mu} {sum}\mspace{14mu} {of}\mspace{14mu} {Removed}_{spl}\mspace{14mu} {from}\mspace{14mu} {all}\mspace{14mu} {previous}\mspace{14mu} {sample}\mspace{14mu} {times}\mspace{14mu} ({mg})}}\mspace{11mu}} \\{{{Scalar} = {{see}\mspace{14mu} {Scalar}\mspace{14mu} {Table}}}\mspace{560mu}} \\{{{Label} = {{The}\mspace{14mu} {labeled}\mspace{14mu} {strength}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {sample}\mspace{14mu} {in}\mspace{14mu} {mg}}}\mspace{290mu}}\end{matrix}$

Scalar Table Sample Point (minutes) Scalar 5 900 10 890 20 880 30 870 40860

1.17.10.4 Calculation Notes

-   Many HPLC systems and data systems will perform some or all of the    calculations automatically. These systems should be spot checked    manually to determine that they perform calculations as expected.

3.17.11 Tolerance

-   NLT 80% of the labeled amount (Q) of topiramate (C12H21NO8S) is    dissolved in 40 minutes (average, n=6 or 12). Report % RSD.

1.18 Microbial Testing (USP <61>)

1.18.1 Equipment

ITEM EQUIPMENT Manufacturer/Model* Asset Number 1 CO₂ IncubatorSanyo/MCO20AIC LIF-0001 2 CO₂ Incubator Sanyo/MCO20AIC LIF-0049 *Orsimilar calibrated/qualified equipment

1.18.2 Reagents and Standards

VENDOR/CATALOG ITEM Reagents and Materials NUMBER** 1 HeterotrophicPlate Count Millipore/MHPC10025 Sampler (HPC, Red) 2 Yeast and MoldSampler Millipore/MHPC10025 (YM, Yellow) **Or equivalent

1.18.3 Challenge Organisms for Positive Controls

ATCC Number Aerobic bacteria Staphylococcus aureus ATCC 6538 Bacillusspizizenii ATCC 6633 Pseudomonas aeruginosa ATCC 9027 Anaerobicbacterium Clostridium sporogenes ATCC 19404 Fungi Candida albicans ATCC10231 Aspergillus brasiliensis ATCC 16404

1.18.4 Procedure

-   Note: This procedure should be completed under sterile laboratory    conditions.-   Disinfect the outer package of each test article, HPC and YM    samplers prior to testing using a sterile clean room wipe moistened    with a germicidal. Write on the Sampler case with indelible marker    the date and sample identification information. Open the Sampler    package, lift out the sampler and carefully remove the paddle from    its case. Pour the Sample liquid into the sample case, filling the    upper (18 mL) graduation. Insert the Sampler firmly into the case    containing sample, and carefully lay the unit with the membrane    facing down onto a flat surface. Make sure the membrane is uniformly    wetted, and while in this position, the unit should not be agitated.    Allow 30 seconds for sample to be drawn through the filter and    ensure there are no more bubbles coming out of the vent prior to    removing the paddle from the sample. Remove the paddle and, with a    firm snap of the wrist, shake off the excess liquid. Empty the case    and re-insert the paddle. Ensure that the paddle is seated firmly in    the case to form an airtight seal.-   Incubate the HPC Sampler at 30-35° C. for 48-72 hours and the YM    Sampler 20-25° C. for 24-72 hours, with the gridded side facing    down. Examine both samplers after an initial 24 hours (and    thereafter, every 24 hours) and obtain images of both the sample    information on the sampler case and the gridded side of the sampler.

1.18.5 Negative Controls

-   Incubate fresh HPC Sampler at 30-35° C. for 48-72 hours and the YM    Sampler 20-25° C. for 24-72 hours, with the gridded side facing    down. Examine both samplers after an initial 24 hours (and    thereafter, every 24 hours) and obtain images of both the sample    information on the sampler case and the gridded side of the sampler.

1.18.6 Preparation of Positive Controls

-   Prepare the following:-   Handling bacteria requires full gowning, head and toe, the use of    sterile gloves only and work in the hood. The hood requires full    cleaning with peroxide and alcohol. Take some contact plates before,    and sedimentation plates during processing. Full gowning, with face    and hands control, followed by cleaning well after the work are    important.-   Growth promotion test with EZ-Accu Shot™ microorganisms:    -   1. INTENDED USE of EZ-Accushot:-   EZ-Accu Shot™ Microorganisms are lyophilized, quantitative    microorganism preparations to be used for Quality Control purposes.    Processed as directed, these preparations provide a challenge of    <100 CFU per 0.1 mL. This is the required concentration for growth    promotion testing of culture media to be employed in most microbial    enumeration tests, tests for specified microorganisms, and sterility    tests. These microorganism preparations are traceable to the    American Type Culture Collection (ATCC®) or other authentic    reference culture collections.    -   (Record lot number, ATCC numbers and how prepared)    -   2. SPECIFICATIONS AND PERFORMANCE:-   EZ-Accu Shot™ Microorganisms are packaged in a kit configuration.    Each kit consists of:    -   Five (5) vials each containing one (1) lyophilized pellet of an        individual microorganism strain    -   Five (5) Hydrating Fluid vials each containing 1.2 mL of        hydrating fluid    -   Detailed instructions    -   Certificate of Assay    -   3. Processed as directed, EZ-Accu Shot™ Microorganisms will        provide a challenge concentration of <100 CFU per 0.1 mL.        Quality control documentation includes, but is not limited to, a        Certificate of Assay stating:        -   The identity of the microorganism        -   The traceability of the microorganism to a reference culture        -   That the microorganism preparation has been removed not more            than four (4) passages from the reference culture        -   The mean assay value for the microorganism preparation

Precautions and Limitations

-   These products are for in-vitro use only. These devices, and    subsequent growth of these microorganisms on culture media, are    considered to be biohazard material. These devices contain viable    microorganisms that may, under certain circumstances, produce    disease. Proper techniques must be employed to avoid exposure and    contact with any microorganism growth.    -   The microbiology laboratory must be equipped, and have the        facilities to receive, process, maintain, store and dispose of        biohazard, material.    -   Microbiology laboratory personnel using these devices must be        educated, experienced and demonstrate proficiency in processing,        maintaining, storing and disposing of biohazard material.    -   Agencies and statutes do regulate the disposal of all biohazard        materials. Each laboratory must be aware of, and comply with,        the proper disposal of biohazard materials

A. Material Preparation

All the materials required for the challenge procedure and the materialsto be challenged must be ready for use immediately following thehydration step. Following the hydration of the lyophilized strain,challenge inoculation(s) MUST be completed within 8 hours. The remainingsuspension must be refrigerated at 2-8° C. between use to avoid a changein the challenge suspension concentration.

B. Hydration

-   -   1. Remove the Hydrating Fluid vial and vial containing        lyophilized strain preparation (pellet) from refrigerated        storage. Allow the lyophilized strain preparation and the        Hydrating Fluid to equilibrate to room temperature.    -   2. Transfer ONE (1) pellet into the 1.2 mL vial of Hydrating        Fluid under aseptic condition    -   3. ONLY ONE PELLET MUST BE USED TO OBTAIN THE CHALLENGE        CONCENTRATION OF <100 CFU per 0.1 mL.    -   4. Immediately recap the vial with the hydrated material.    -   5. Vortex the hydrated material to achieve a homogeneous        suspension.    -   6. Refrigerate suspension at 2-8° C. if not used right away.

C. Inoculation

-   -   1. Under aseptic condition, use a 1 mL syringe (graduated every        0.1 mL) equipped with a sterile needle.    -   2. Inject 0.1 mL of the inoculum into each medium to be        challenged.    -   3. Proceed with the challenge procedure according to laboratory        protocol.    -   4. Refrigerate suspension in the syringe at 2-8° C. if it will        be used again.    -   5. Discard any remaining hydrated material in accordance with        the laboratory protocol for disposal of biohazard materials.

-   Fill each sampler to the 18 mL mark with sterile water for    injection. Inoculate the HPC Sampler with S. aureus, P.    aeruginosa, B. subtilis, and C. sporogene and incubate at 30-35° C.    for at least 48 hours.

-   Inoculate the YMSampler with C. albicans, and A. brasiliensis and    incubated at 20-25° C. for 4 days.

1.18.7 Sampler Examination

-   For the HPC Samplers, colonies appear glistening and translucent or    transparent. Colors vary from colorless to white, cream yellow or    occasionally pigmented. Magnification of colonies is recommended for    counting colonies. Mold colonies appear white, green or brown/black    and filamentous. Bacterial colonies may appear but are usually    smaller and more glistening and transparent than the yeast colonies.

1.18.8 Tolerance

-   The sample should meet the following specifications:

Total Aerobic Microbial Count (TAMC) ≤100 cfu/mL Combined Yeasts andMolds (TYMC) ≤10 cfu/mL

Example 6 Storage Stability Test

The storage stability of the suspension has been tested over a 6-monthstorage period under accelerated conditions 40° C. and 75% RH for aperiod of 6 months and for 24 months at 25° C. and 60% RH. Sufficientbottles of 236 mL bottles were stored at these conditions at each timepoint of the stability program the composition of suspension wasanalyzed by HPLC chromatography and the amount of topiramate and itsknown impurities were determined by a validated HPLC assay. Other testssuch as sedimentation rate or redispersibility, during the storageperiod.

Example 7 Pharmacokinetics (PK)

Pharmacokinetics (PK) of topiramate were obtained after administrationof a single dose of oral liquid suspension in a human volunteer, usingthe following protocols.

Synopsis of PK Studies

1.0 Protocol Summary—Pilot Study—Fasting Condition

Study Title An open-label, randomized, balanced, single-dose,two-treatment, two-period, two-sequence, cross-over, oralbioavailability study of Topiramate oral suspension 25 mg/mLManufactured by OWP Pharmaceuticals, Inc, 400 East Diehl Road, Suite400, Naperville, IL 60563 with TOPAMAX ® (topiramate) tablets, 100 mgmanufactured by Janssen Ortho LLC Gurabo, Puerto Rico 00778 andmanufactured for Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 inhealthy, adult, human, male subjects under fasting conditions. StudyObjectives 1. To compare the oral bioavailability of Topiramate oralsuspension 25 mg/mL of OWP Pharmaceuticals, Inc, 400 East Diehl Road,Suite 400, Naperville, IL 60563 with TOPAMAX ® (Topiramate) tablets, 100mg manufactured by Janssen Ortho LLC Gurabo, Puerto Rico 00778 andmanufactured for Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 inhealthy, adult, human, male subjects under fasting conditions. 2. Toevaluate subject safety and tolerability of investigational products.Study Design An open-label, randomized, balanced, single-dose,two-treatment, two-period, two-sequence, cross-over, oral bioequivalencestudy in 18 healthy, adult, human, male subjects under fastingconditions. Number of Eighteen (18) healthy, adult, human, male subjectswill be enrolled Subjects into the study. One additional subject will beenrolled to compensate for any withdrawn/dropout prior to the dosing ofPeriod-I. If any subject withdraws/drops out due to any reason prior tothe dosing in Period- I, he will be replaced with the additionalenrolled subject to ensure the dosing of 18 subjects as per in-houseSOP. Investigational Test (T) Topiramate oral suspension 25 mg/mL DrugProducts Manufactured by: OWP Pharmaceuticals, Inc, 400 East Diehl Road,Suite 400, Naperville, IL 60563 Reference TOPAMAX ® (Topiramate)tablets, 100 mg (R) Manufactured by: Janssen Ortho, LLC Gurabo, PuertoRico 00778. Manufactured for: Janssen Pharmaceuticals, Inc. Titusville,NJ 08560. Drug Subjects should comply at least 10.00 hours overnightfasting prior Administration to drug administration and no food will beallowed at least 4.00 hours post dose in each period. As per therandomization schedule, subject will receive Test or reference productin each period. Subjects will receive Test product once and Referenceproduct once by end of the study. The clock time when each dose isadministered will be recorded on the Case Report Forms. ReferenceProduct Administration: One tablet of reference product [Topamax ®(Topiramate) tablets 100 mg] will be administrated to the subject with240 ± 02 mL of drinking water at room temperature in sitting posture,under fasting conditions. Subjects will be instructed do not chew,crash, or break the tablet and swallow whole. The clinical staff willensure that the study participant has swallowed the medication byperforming mouth check using torchlight and Spatula/tongue depressor.Test product Administration: 4 mL of test product (topiramate oralsuspension 25 mg/mL) will be slowly administered orally, directly intothe corner of the mouth until the liquid medicine in the syringe iscompleted, to the subjects using a disposable graded syringe at roomtemperature in sitting posture, under fasting conditions. After subjectsswallow oral suspension, the drag-dispensing container (syringe) will berinsed with an adequate amount of water until it is free of medicine andallowed to swallow the rinse. The remaining amount of water from 240 ±02 mL will be administered at room temperature in sitting posture, underfasting condition. Subjects will be instructed do not spit thesuspension and swallow entirely (as a whole dosage). Admission and Studyparticipants will be housed in the Clinical Pharmacology Unit Stay (CPU)from at least 11.00 hours before drug administration to 48.00 hoursafter drug administration. Sample Time Points Sampling Time In eachperiod, total 22 (1 × 4 mL) blood samples will be collected Points asper the following schedule: Pre dose (0.00 hour) sample will becollected within 01 hour prior to drug administration and the post dosesamples will be collected at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75,2.00, 2.50, 3.00, 3.50, 4.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00,36.00, 48.00 and 72.00 hours into 4 ml K₂EDTAvacutainers. In-houseAmbulatory Total 21 01 22 Blood Loss Screening Up to 12 mL Study 176 mLDiscarding the Saline mixed blood Up to 17 mL Post Study Up to 12 mLTotal Approximately 217 mL. Anticoagulant K₂EDTA Centrifugation 3800 RPMfor 10 minutes at 4° C. ± 2° C. Details Sample Storage Samples will bestored at −70° C. ± 15° C. until drawn for analysis. Conditions No. ofAliquots Two Analytical The plasma concentration of Topiramate will bequantified in Methods plasma using validated analytical method.Pharmacokinetic Primary Parameters: C_(max) AUC_(0-t) and AUC_(0-inf)Parameters Secondary Parameters: T_(max), K_(el) and t_(1/2).Bioequivalence Based on the Analysis, Bioequivalence is declared if theTest Criteria products (T) and Reference (R) ratios of the geometricleast squares means for ln-transformed pharmacokinetic parametersC_(max), AUC_(0-t) and AUC_(0-inf) and their 90% confidence intervalsare within 80.00%- 125.00% for Topiramate. Ethical Issues The study willcommence only after a written approval is obtained from the EthicsCommittee (EC). The study will be conducted as per New Drugs andClinical Trials Rules 2019 G.S.R 227(E) dated: 19 Mar. 2019; EthicalGuidelines for Biomedical Research on Human Participants, Good ClinicalLaboratory Practice (GCLP), ICMR (Indian Council of Medical Research;2017), Declaration of Helsinki (64^(th) WMA General Assembly, Fortaleza,Brazil, October 2013), ICH E6 R2 (Step 5) ‘Guidance on Good ClinicalPractice’, Guidance for Industry Bioavailability and BioequivalenceStudies for Orally Administered Drug Products - General Considerations -U. S. Department of Health and Human Service Food and DrugAdministration, Center for Drug Evaluation and Research (CDER) March2003; 21 CFR (Code of Federal Regulations) and all other applicableregulatory requirements.

2.0 Protocol Summary—Pilot Study—Food Effect

Study Title An open-label, balanced, randomized, single-dose,two-treatment, three-period, six-sequence, cross-over, oral food effectand fed comparative bioavailability and bioequivalence study ofTopiramate oral suspension 25 mg/mL of OWP Pharmaceuticals, Inc, 400East Diehl Road, Suite 400, Naperville, IL 60563, with TOPAMAX ®(Topiramate) tablets, 100 mg manufactured by Janssen Ortho LLC Gurabo,Puerto Rico 00778 and manufactured for Janssen Pharmaceuticals, Inc.Titusville, NJ 08560 in healthy, adult, human, male subjects. StudyObjectives 1. To compare the rate and extent of absorption of TopiramateOral Suspension 25 mg/mL of OWP Pharmaceuticals, Inc, 400 East DiehlRoad, Suite 400, Naperville, IL 60563 with TOPAMAX ® (Topiramate)tablets 100 mg manufactured by Janssen Ortho LLC Gurabo, Puerto Rico00778 and manufactured for Janssen Pharmaceuticals, Inc. Titusville, NJ08560 in healthy, adult, human, male subjects under fed condition. 2. Toevaluate the effect of food on the rate and extent of absorption ofTopiramate Oral Suspension 25 mg/mL of OWP Pharmaceuticals, Inc, 400East Diehl Road, Suite 400, Naperville, IL 60563 in healthy, adult,human, male subjects. 3. To evaluate the subject safety and tolerabilityof investigational products. Study Design An open label, balanced,randomized, single-dose, two-treatment, three-period, six-sequence,cross-over, oral food effect and fed comparative bioequivalence study in36 healthy adult human male subjects. Number of Thirty-Six (36) healthy,adult, human male subjects will be enrolled Subjects into the study. Twoadditional subjects will be enrolled to compensate for anywithdrawn/dropout prior to the dosing of Period-I. If any subjectwithdraws/drops out due to any reason prior to the dosing in Period- I,he will be replaced with the additional enrolled subject to ensure thedosing of 36 subjects as per in-house SOP. Investigational Test (T)Topiramate oral suspension 25 mg/mL Drug Products Manufactured by: OWPPharmaceuticals, Inc, 400 East Diehl Road, Suite 400, Naperville, IL60563 Reference TOPAMAχ ® (Topiramate) tablets, 100 mg (R) Manufacturedby: Janssen Ortho, LLC Gurabo, Puerto Rico 00778 Manufactured for:Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Washout Period Atleast 21 days, between each drug administration Duration of the Theminimum duration of this study will be at least 47 days study (includinga gap of washout period of 21 days between each periods of the study).Drug As per the randomization schedule, each subject will receive TestAdministration product (T) twice and Reference product (R) once as perrandomization cross-over design by end of the study The clock time wheneach dose is administered will be recorded on the Case Report Forms.Test Treatment Fasting conditions: After an overnight fasting of atleast 10.00 hours prior to administration. Test Treatment Fed condition:After an overnight fasting of at least 10.00 hours, a high fat and highcalorie breakfast will be served 30 minutes prior to administration.Reference Treatment Fed condition: After an overnight fasting of atleast 10.00 hours, a high fat high calorie breakfast will be served 30minutes prior to administration. Test Treatment Fasting conditions: 4 mLof test product (topiramate oral suspension 25 mg/mL) will be slowlyadministered orally, directly into the corner of the mouth until theliquid medicine in the syringe is completed, to the subjects using adisposable graded syringe at room temperature in sitting posture, underfasting conditions. After subjects swallow oral suspension, thedrug-dispensing container (syringe) will be rinsed with an adequateamount of water until it is free of medicine and allowed to swallow therinse. The remaining amount of water from 240 ± 02 mL will beadministered at room temperature in sitting posture, under fastingcondition. Subjects will be instructed do not spit the suspension andswallow entirely (as a whole dosage). Test Treatment Fed condition: 4 mLof test product (Topiramate oral suspension 25 mg/mL) will be slowlyadministered orally, directly into the corner of the mouth until theliquid medicine in the syringe is completed, to the subjects using adisposable graded syringe at room temperature in sitting posture, underfed conditions. After subjects swallow oral suspension, thedrug-dispensing container (syringe) will be rinsed with an adequateamount of water until it is free of medicine and allowed to swallow therinse. The remaining amount of water from 240 ± 02 mL will beadministered at room temperature in sitting posture. Subjects will beinstructed do not spit the suspension and swallow whole. ReferenceTreatment Fed condition: One tablet of reference product (TOPAMAX ®(Topiramate) tablets, 100 mg) will be administered to the subjects insitting posture with 240 ± 02 mL water, under fed conditions. Subjectswill be instructed do not chew or crush the tablet and swallow whole.The clinical staff will ensure that the study participant has swallowedthe medication by performing mouth check using torchlight andSpatula/tongue depressor. Admission and Study participants will behoused in the Clinical Pharmacology Unit Stay (CPU) from at least 11.00hours before drug administration to 48.00 hours after drugadministration. Sample Management Sampling Time In each period, total 22(1 × 4 mL) blood samples will be collected as Points per the followingschedule: Pre dose (0.00 hour) sample will be collected within 01 hourprior to drug administration and the post dose samples will be collectedat 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50,4.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 and 72.00hours into 4 ml K2EDTAvacutainers. In-house Ambulatory Total 21 01 22Blood Loss Screening Up to 12 mL Study 264 mL Discarding the Salinemixed blood Up to 26 mL Post Study Up to 12 mL Total Approximately 314mL Anticoagulant K₂EDTA Centrifugation 3800 RPM for 10 minutes at 4° C.± 2° C. Details Sample Storage Plasma samples will be stored at −70° C.± 15° C. until drawn for Conditions bioanalysis. No. of Aliquots TwoAnalytical The plasma concentrations of Topiramate will be quantified inplasma Methods using validated analytical method. PharmacokineticPrimary Parameters: C_(max) AUC_(0-t) and AUC_(0-inf) ParametersSecondary Parameters: T_(max), K_(el) and t_(1/2). Criteria for Based onthe statistical results of 90% confidence interval for the Evaluationratio of the geometric least squares mean for log-transformedpharmacokinetic parameters C_(max), AUC_(0-t), and AUC_(0-inf) forTopiramate conclusion will be drawn for Test (fed) versus Reference(fed) and Test (fasting) versus Test (fed) treatment. Absence of foodeffect on bioavailability of test product will be established if the 90percent confidence intervals for the ratio of population geometric meansbetween Test (fasting) and Test (fed) treatments, based onlog-transformed data, are contained in the equivalence limits of80.00-125.00% for C_(max) and AUC₀₋₇₂. The test product (Fed) will beconcluded bioequivalent to the Reference product (Fed ) if the limitsfall within acceptance range (80.00%-125.00%) of the 90% confidenceintervals for the difference of means of log-transformed (Cmax andAUC0-72) with respect to Topiramate. Ethical Issues The study willcommence only after a written approval is obtained from the EthicsCommittee (EC). The study will be conducted as per New Drugs andClinical Trials Rules 2019 G.S.R 227(E) dated: 19 Mar. 2019; EthicalGuidelines for Biomedical Research on Human Participants, Good ClinicalLaboratory Practice (GCLP), ICMR (Indian Council of Medical Research;2017), Declaration of Helsinki (64^(th) WMA General Assembly, Fortaleza,Brazil, October 2013), ICH E6 R2 (Step 5) ‘Guidance on Good ClinicalPractice’, Guidance for Industry Bioavailability and BioequivalenceStudies for Orally Administered Drag Products - General Considerations -U. S. Department of Health and Human Service Food and DrugAdministration, Center for Drug Evaluation and Research (CDER) March2003; 21 CFR (Code of Federal Regulations) and all other applicableregulatory requirements.

1.0 Pivotal Study—Protocol Summary—Fasting Study

Study Title An open-label, randomized, balanced, single-dose,two-treatment, two-period, two-sequence, two-way cross-over, oralbioavailability study of Topiramate oral suspension 25 mg/mLManufactured by OWP Pharmaceuticals, Inc, 400 East Diehl Road, Suite400, Naperville, IL 60563 with TOPAMAX ® (topiramate) tablets, 100 mgmanufactured by Janssen Ortho LLC Gurabo, Puerto Rico 00778 andmanufactured for Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 inhealthy, adult, human, male subjects under fasting conditions. StudyObjectives 1. To compare the oral bioavailability of Topiramate oralsuspension 25 mg/mL Manufactured by OWP Pharmaceuticals, Inc, 400 EastDiehl Road, Suite 400, Naperville, IL 60563 with TOPAMAX ® (topiramate)tablets 100 mg manufactured by Janssen Ortho LLC Gurabo, Puerto Rico00778 and manufactured for Janssen Pharmaceuticals, Inc. Titusville, NJ08560 in healthy, adult, human, male subjects under fasting conditions.2. To evaluate subject safety and tolerability of investigationalproducts. Study Design An open-label, randomized, balanced, single-dose,two-treatment, two-period, two-sequence, cross-over, oral bioequivalencestudy in 36 healthy, adult, human, male subjects under fastingconditions. Number of Thirty-six (36) healthy, adult, human, malesubjects will be enrolled Subjects into the study. Two additionalsubjects will be enrolled to compensate any withdrawn/dropout prior tothe dosing of Period-I. If any subject withdraws/drops out due to anyreason prior to the dosing in Period- I, he will be replaced with theadditional enrolled subjects to ensure the dosing of 36 subjects as perin-house SOP. Investigational Test (T) Topiramate oral suspension 25mg/mL Drug Products Manufactured by: OWP Pharmaceuticals, Inc, 400 EastDiehl Road, Suite 400, Naperville, IL 60563 Reference TOPAMAX ®(topiramate) tablets, 100 mg (R) Manufactured by: Janssen Ortho, LLCGurabo, Puerto Rico 00778 Manufactured for: Janssen Pharmaceuticals,Inc. Titusville, NJ 08560 Washout Period At least 21 days, between eachdrug administration. Duration of the The minimum duration of this studywill be at least 26 days period (including a gap of washout period of 21days between each period of the study). Drug Subjects should comply atleast 10.00 hours overnight fasting prior Administration to drugadministration and no food will be allowed at least 4.00 hours post dosein each period. As per the randomization schedule subject will receiveTest or Reference product in each period. Subjects will receive Test (T)treatment once and Reference (R) treatment once The clock time when eachdose is administered will be recorded on the Case Report Forms.Reference Product Administration: One tablet of reference product[TOPAMAχ ® (topiramate) tablets, 100 mg] will be administrated to thesubject with 240 ± 02 mL of drinking water at room temperature insitting posture, under fasting conditions. Subjects will be instructeddo not chew, crush, or break the tablet and swallow whole. The clinicalstaff will ensure that the study participant has swallowed themedication by performing mouth check using torchlight and Spatula/tonguedepressor. Test product Administration: 4 mL of test product (Topiramateoral suspension 25 mg/mL) will be slowly administered orally, directlyinto the comer of the mouth until the liquid medicine in the syringe iscompleted, to the subjects using a disposable graded syringe at roomtemperature in sitting posture, under fasted conditions. After subjectsswallow oral suspension, the drug-dispensing container (syringe) will berinsed with an adequate amount of water until it is free of medicine andallowed to swallow the rinse. The remaining amount of water from 240 ±02 mL will be administered at room temperature in sitting posture, underfasting condition. Subjects will be instructed do not spit thesuspension and swallow whole. Admission and Study participants will behoused in the Clinical Pharmacology Unit Stay (CPU) from at least 11.00hours before drug administration to 48.00 hours after drugadministration. Sample Management Sampling Time In each period, total 22(1 × 4 mL) blood samples will be collected Points as per the followingschedule: Pre dose (0.00 hour) sample will be collected within 01 hourprior to drug administration and the post dose samples will be collectedat 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50,4.00, 6.00, 8.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 and 72.00hours into 4 ml K₂EDTAvacutainers In-house Ambulatory Total 21 01 22Blood Loss Screening Up to 12 mL Study 176 mL Discarding the Salinemixed blood Up to 17 mL Post Study Up to 12 mL Total Approximately 217mL Anticoagulant K₂EDTA Centrifugation 3800 RPM for 10 minutes at 4° C.± 2° C. Details Sample Storage samples will be stored at −70° C. ± 15°C. until drawn for bioanalysis. Conditions No. of Aliquots TwoAnalytical The plasma concentrations of Topiramate will be quantified inMethods plasma using validated analytical method. PharmacokineticPrimary Parameters: C_(max) AUC_(0-t), and AUC_(0-inf) ParametersSecondary Parameters: T_(max), K_(el) and t_(1/2). Bioequivalence Basedon the Analysis, Bioequivalence is declared if the Test Criteriaproducts (T) and Reference (R) ratios of the geometric least squaresmeans for ln-transformed pharmacokinetic parameters C_(max), AUC_(0-t)and AUC_(0-inf) and their 90% confidence intervals are within 80.00%-125.00% for Topiramate. Ethical Issues The study will commence onlyafter a written approval is obtained from the Ethics Committee (EC). Thestudy will be conducted as per New Drugs and Clinical Trials Rules 2019G.S.R 227(E) dated: 19 Mar. 2019; Ethical Guidelines for BiomedicalResearch on Human Participants, Good Clinical Laboratory Practice(GCLP), ICMR (Indian Council of Medical Research; 2017), Declaration ofHelsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013),ICH E6 R2 (Step 5) ‘Guidance on Good Clinical Practice’, Guidance forIndustry Bioavailability and Bioequivalence Studies for OrallyAdministered Drug Products - General Considerations - U. S. Departmentof Health and Human Service Food and Drug Administration, Center forDrug Evaluation and Research (CDER) March 2003, 21 CFR (Code of FederalRegulations) and all other applicable regulatory requirements.

Timetable of Events (Example)

-   The following is a representative time schedule for one subject    assuming that the study medication will be administered at 08:00. A    wash out period of 07 days will be maintained between each drug    administration. Timings for other subjects will be uniformly    staggered:

TIME RELATIVE TO DOSING APPROXIMATE DAY (HOURS) TIME EVENTS 1 −24.00 to−11.00 08:00 to 21:00 Compliance Assessment, Check-In and Dinner. 1−10.00 to −9.00  22:00 to 23:00 Bedtime 2 −2.50 05:30 Wakeup call 2−2.00 to 0.00   06:00 to 08:00 Pre dose Vitals, Well-being andCannulation 2 −1.00 07:00 Water restriction begins 2 −1.00 to 0.00  07:00 to 08:00 Pre-dose blood sample collection 2 −0.50 07:30 High fatand high calorie breakfast (Only for fed condition) 2 0.00 08:00 Dosing& Posture restriction begins. 2 0.25 08:15 Blood sample collection 20.50 08:30 Blood sample collection 2 0.75 08:45 Blood sample collection2 1.00 09:00 Blood sample collection, Vitals, Well-being & Waterrestriction ends. 2 1.25 09:15 Blood sample collection 2 1.50 09:30Blood sample collection 2 1.75 09:45 Blood sample collection 2 2.0010:00 Blood sample collection 2 2.50 10:30 Blood sample collection 23.00 11:00 Blood sample collection, Orthostatic vitals & Well-being. 23.50 11:30 Blood sample collection 2 4.00 12:00 Blood sample collectionand Lunch 2 5.00 13:00 Blood sample collection 2 6.00 14:00 Blood samplecollection, Orthostatic vitals & Well-being 2 7.00 15:00 Blood samplecollection 2 8.00 16:00 Blood sample collection & Posture restrictionends. 2 09.00 17:00 Snacks 2 10.00 18:00 Blood sample collection, Vitals& Well-being 2 12.00 20:00 Blood sample collection 2 13:00 21:00 Dinner3 16.00 00:00 Blood sample collection 3 24.00 08:00 Blood samplecollection, Vitals & Well-being 3 25.00 09:00 Break fast 3 28.00 12:00Vitals & Well-being 3 29.00 13:00 Lunch 3 33.00 17:00 Snacks 3 36.0020:00 Vitals & Well-being 3 37.00 21:00 Dinner 4 48.00 08:00 Vitals,Well-being, Check out and Post study assessment. Note: Actual time maychange according to the dose administration time.

What is claimed is:
 1. A method for treating at least one of aneurological disorder and a mental disorder in a subject, the methodcomprising administering to a subject suffering from the disorder, 0.1to 25.0 mL of an oral liquid suspension comprising:2,3:4,5-Di-O-isopropylidene-β-D-fluctopyranose sulfamate (topiramate),present in 25±5 mg/mL; water; glycerin; propylene glycol; polyethyleneglycol; methylparaben; sodium benzoate; sorbitol; saccharin; sucralose;xanthan gum; carboxymethyl cellulose (CMC); sodium phosphate; andPROSOLV® SMCC 50M (microcrystalline cellulose and colloidal silicondioxide).
 2. The method of claim 1, wherein the neurological disordercomprises epilepsy.
 3. The method of claim 1, wherein the mentaldisorder comprises bipolar disorder.
 4. The method of claim 1, whereinthe at least one of a neurological disorder and a mental disordercomprises at least one of (a)-(c): (a) epilepsy—adjunctive therapy in asubject aged 2 years or older: partial-onset seizures primarygeneralized tonic-clonic seizures generalized—seizures of Lennox-Gastautsyndrome (b) epilepsy monotherapy in a subject aged 16 years and older:Conversion to monotherapy in a subject with partial-onset seizures whoare receiving treatment with carbamazepine, phenytoin, phenobarbital,primidone, or valproate as the single AED (c) bipolar disorder:maintenance treatment of bipolar I disorder to delay the time tooccurrence of mood episodes in a subject treated for acute mood episodeswith standard therapy.
 5. The method of claim 1, wherein the topiramatepresent in the oral liquid suspension has the following particle sizedistribution (PSD): D₉₀ of not more than 200 microns, D₅₀ of not morethan 100 microns, and D₁₀ of not more than 30 microns.
 6. The method ofclaim 1, wherein the topiramate present in the oral liquid suspensionhas the following particle size distribution (PSD): D₉₀ of not more than139 microns, D₅₀ of not more than 64.8 microns, and D₁₀ of not more than24.65 microns.
 7. The method of claim 1, wherein the oral liquidsuspension has a viscosity at 25° C. of 300-400 mPs.
 8. The method ofclaim 1, wherein the oral liquid suspension has a viscosity at 25° C. of341.7±10 mPs.
 9. The method of claim 1, wherein the oral liquidsuspension has a pH of 7.5-7.9.
 10. The method of claim 1, wherein theoral liquid suspension has a pH of 7.7±0.1.
 11. The method of claim 1,wherein the oral liquid suspension has a specific gravity of not morethan 1.1049.
 12. The method of claim 1, wherein the oral liquidsuspension has a specific gravity of not more than 1.2.
 13. The methodof claim 1, wherein the oral liquid suspension further comprises aflavoring agent.
 14. The method of claim 1, wherein the oral liquidsuspension further comprises cherry flavor as a flavoring agent.
 15. Themethod of claim 1, wherein the oral liquid suspension has furthercomprises a coloring agent.
 16. The method of claim 1, wherein the oralliquid suspension further comprises FD&C red #40 and FD&C yellow #6 as acoloring agent.
 17. The method of claim 1, wherein the oral liquidsuspension comprises: Amount (% w/v) Component  2.5 ± 0.25 topiramate0.10 ± 0.01 methylparaben  0.03 ± 0.003 sodium benzoate powder  0.08 ±0.008 saccharin sodium dihydrate 3.00 ± 0.3  70% solution of sorbitol2.25 ± 0.3  propylene glycol  5 ± 0.5 glycerin (99% natural) 1.26 ± 0.15PROSOLV ® SMCC 50M (microcrystalline cellulose and colloidal silicondioxide) 0.18 ± 0.02 sodium carboxymethyl cellulose (medium viscosity,2% aqueous solution at 25° C. 400-800 cPs) 0.18 ± 0.02 xanthan gum NF0.20 ± 0.02 cherry flavor, natural & artificial  0.002 ± 0.0002 FD&C Red#40  0.0002 ± 0.00002 FD&C Yellow #6 79.67 ± 8.0  purified water  5 ±0.5 polyethylene glycol 400 0.25 ± 0.03 sodium phosphate dibasic (dried) 0.5 ± 0.05 sucralose TOTAL 100.2022


18. The method of claim 1, wherein the oral liquid suspension has avolume of 0.2 mL, 0.5 mL, 2.5 mL, 10 mL, 15 mL, or 20 mL.
 19. The methodof claim 1, wherein the oral liquid suspension, while packaged in acontainer, is essentially free from microbial growth for at least 24months under ambient conditions.
 20. The method of claim 1, wherein theoral liquid suspension, while packaged in a container, is essentiallyfree from Escherichia coli (E. coli) for at least 24 months underambient conditions.
 21. The method of claim 1, wherein the oral liquidsuspension, while packaged in a container, is essentially free fromBurkholderia cepacia complex (BCC) for at least 24 months under ambientconditions.
 22. The method of claim 1, wherein the oral liquidsuspension is an immediate release dosage form.
 23. The method of claim1, wherein the oral liquid suspension is an immediate release dosageform that exhibits in-vitro dissolution rate more than 88% of drugrelease within 30 minutes, when said dosage form is placed in adissolution vessel filled with 900 ml of 0.1N HCL, pH 1.2 maintained at37±0.5° C. and stirred at a paddle speed of 50 rpm using a USP Type II(paddle) apparatus.
 24. The method of claim 1, wherein the oral liquidsuspension is administered, such that 2.5±0.25 mg topiramate in 0.1 mLof the oral liquid suspension, or 5±0.5 mg topiramate in 0.2 mL of theoral liquid suspension, or 10±1.0 mg topiramate in 0.4 mL of the oralliquid suspension, or 12.5±1.25 mg topiramate in 0.5 mL of the oralliquid suspension, or 15±1.5 mg topiramate in 0.6 mL of the oral liquidsuspension, or 20±2.0 mg topiramate in 0.8 mL of the oral liquidsuspension, or 25±2.5 mg topiramate in 1.0 mL of the oral liquidsuspension, or 50±5.0 mg topiramate in 2.0 mL of the oral liquidsuspension, or 62.5±6.25 mg topiramate in 2.5 mL of the oral liquidsuspension, or 75±7.5 mg topiramate in 3.0 mL of the oral liquidsuspension, or 100±10.0 mg topiramate in 4.0 mL of the oral liquidsuspension, or 125±12.5 mg topiramate in 5.0 mL of the oral liquidsuspension, or 150±15.0 mg topiramate in 6.0 mL of the oral liquidsuspension, or 175±17.5 mg topiramate in 7.0 mL of the oral liquidsuspension, or 200±20.0 mg topiramate in 8.0 mL of the oral liquidsuspension, or 250±25.0 mg topiramate in 10.0 mL of the oral liquidsuspension is delivered to the subject.
 25. The method of claim 1,wherein upon administration under fasted conditions of a healthy adultsubject with epilepsy taking no other medications, the oral liquidsuspension exhibits a single-dose administration pharmacokinetic (;PK)profile including: AUC, 0→24 (micrograms per ml) of 98-105; Cmax(micrograms per ml) steady state of 1.5; T_(max)(h) of 2-3; t_(1/2)(h)of 19-25 (single dose); and t_(1/2)(h) of 19-25 (multiple dose).
 26. Themethod of claim 1, wherein relative to oral tablets or chewabledispersible tablets containing an equivalent amount of topiramate,administration of the oral liquid suspension results in a lowerincidence, severity, and/or duration of adverse reactions including atleast one of dizziness, headache, diplopia, ataxia, nausea, blurredvision, somnolence, rhinitis, pharyngitis, rash, vomiting, infection,fever, accidental injury, diarrhea, abdominal pain, tremor, insomnia,somnolence, backpain, fatigue, abdominal pain, and xerostomia.